Deep models of superficial face judgments.

The diversity of human faces and the contexts in which they appear gives rise to an expansive stimulus space over which people infer psychological traits (e.g., trustworthiness or alertness) and other attributes (e.g., age or adiposity). Machine learning methods, in particular deep neural networks, provide expressive feature representations of face stimuli, but the correspondence between these representations and various human attribute inferences is difficult to determine because the former are high-dimensional vectors produced via black-box optimization algorithms. Here we combine deep generative image models with over 1 million judgments to model inferences of more than 30 attributes over a comprehensive latent face space. The predictive accuracy of our model approaches human interrater reliability, which simulations suggest would not have been possible with fewer faces, fewer judgments, or lower-dimensional feature representations. Our model can be used to predict and manipulate inferences with respect to arbitrary face photographs or to generate synthetic photorealistic face stimuli that evoke impressions tuned along the modeled attributes.

Scaling up psychology via Scientific Regret Minimization.

Do large datasets provide value to psychologists? Without a systematic methodology for working with such datasets, there is a valid concern that analyses will produce noise artifacts rather than true effects. In this paper, we offer a way to enable researchers to systematically build models and identify novel phenomena in large datasets. One traditional approach is to analyze the residuals of models-the biggest errors they make in predicting the data-to discover what might be missing from those models. However, once a dataset is sufficiently large, machine learning algorithms approximate the true underlying function better than the data, suggesting, instead, that the predictions of these data-driven models should be used to guide model building. We call this approach "Scientific Regret Minimization" (SRM), as it focuses on minimizing errors for cases that we know should have been predictable. We apply this exploratory method on a subset of the Moral Machine dataset, a public collection of roughly 40 million moral decisions. Using SRM, we find that incorporating a set of deontological principles that capture dimensions along which groups of agents can vary (e.g., sex and age) improves a computational model of human moral judgment. Furthermore, we are able to identify and independently validate three interesting moral phenomena: criminal dehumanization, age of responsibility, and asymmetric notions of responsibility.

Rapid, Quantitative Nuclear Magnetic Resonance Test for Oxygen-17 Enrichment in Water.

Nuclear magnetic resonance (NMR) studies involving 17O are increasingly important in molecular biology, material science, and other disciplines. A large number of these studies employ H217O as a source of 17O, and this reliance can be limiting because the high cost of H217O. To overcome this constraint, a recent study proposed a distillation scheme capable of producing significant quantities of H217O at a low cost. Although this method is reported to be effective, the reactions proposed to quantify percent of 17O enrichment are either time intensive or have a risk of errors due to the isotope effect. Here, an alternative reaction scheme is described to measure 17O water that ultimately creates methyl benzoate as the sole 17O-containing product. The proposed reaction is completed in a matter of minutes at room temperature, produces only one 17O product, and requires no clean-up step. The large isotope shift observed in solution NMR between the 13C═16O and 13C═17O resonances allows for integration of the individual peaks. This 13C NMR analysis is found to be highly accurate over a wide enrichment range and is accessible to most NMR spectroscopists.

Galunisertib Exerts Antifibrotic Effects on TGF-ß-Induced Fibroproliferative Dermal Fibroblasts.

Dermal fibroblasts in pathological scars secrete constitutively elevated levels of TGF-ß, signaling the transcription of fibrotic genes via activin-like kinase 5 (ALK5). In the present study, we examine the antifibrotic effects of galunisertib, a small-molecule inhibitor of ALK5, on fibroproliferative dermal fibroblasts in an in vitro model of wound healing. We induced fibrosis in human dermal fibroblasts with exogenous TGF-ß and performed cellular proliferation assays after treatment with varying concentrations of galunisertib. Dermal fibroblast proliferation was diminished to homeostatic levels without cytotoxicity at concentrations as high as 10 µM. An in vitro scratch assay revealed that galunisertib significantly enhanced cellular migration and in vitro wound closure beginning 24 h post-injury. A gene expression analysis demonstrated a significant attenuation of fibrotic gene expression, including collagen-1a, alpha-smooth muscle actin, fibronectin, and connective tissue growth factor, with increased expression of the antifibrotic genes MMP1 and decorin. Protein synthesis assays confirmed drug activity and corroborated the transcription findings. In summary, galunisertib simultaneously exerts antifibrotic effects on dermal fibroblasts while enhancing rates of in vitro wound closure. Galunisertib has already completed phase II clinical trials for cancer therapy with minimal adverse effects and is a promising candidate for the treatment and prevention of pathological cutaneous scars.

Spin Delocalization, Polarization, and London Dispersion Forces Govern the Formation of Diradical Pimers.

Some free radicals are stable enough to be isolated, but most are either unstable transient species or exist as metastable species in equilibrium with a dimeric form, usually a spin-paired sigma dimer or a pi dimer (pimer). To gain insight into the different modes of dimerization, we synthesized and evaluated a library of 15 aryl dicyanomethyl radicals in order to probe what structural and molecular parameters lead to σ- versus π-dimerization. We evaluated the divergent dimerization behavior by measuring the strength of each radical association by variable-temperature electron paramagnetic resonance spectroscopy, determining the mode of dimerization (σ- or π-dimer) by UV-vis spectroscopy and X-ray crystallography, and performing computational analysis. We evaluated three different hypotheses to explain the difference in the dimerization behavior: (1) that the dimerization behavior is dictated by radical spin densities; (2) that it is dictated by radical polarizability; (3) that it is dictated by London dispersion stabilization of the pimer. However, no single parameter model in itself was predictive. Two-parameter models incorporating either the computed degree of spin delocalization or the radical polarizability as well as computed estimates for the attractive London dispersion forces in the π-dimers lead to improved forecasts of σ- vs π-dimerization mode, and suggest that a balance of spin delocalization of the isolated radical as well as attractive forces between the stacked radicals, govern the formation of diradical pimers.

Correction: Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

PURPOSE: Genotype-guided antiplatelet therapy is increasingly being incorporated into clinical care. The purpose of this study is to determine the extent to which patients initially genotyped for CYP2C19 to guide antiplatelet therapy were prescribed additional medications affected by CYP2C19. METHODS: We assembled a cohort of patients from eight sites performingCYP2C19 genotyping to inform antiplatelet therapy. Medication orders were evaluated from time of genotyping through one year. The primary endpoint was the proportion of patients prescribed two or more CYP2C19 substrates. Secondary endpoints were the proportion of patients with a drug-genotype interaction and time to receiving a CYP2C19 substrate. RESULTS: Nine thousand one hundred ninety-one genotyped patients (17% nonwhite) with a mean age of 68 ± 3 years were evaluated; 4701 (51%) of patients received two or more CYP2C19 substrates and 3835 (42%) of patients had a drug-genotype interaction. The average time between genotyping and CYP2C19 substrate other than antiplatelet therapy was 25 ± 10 days. CONCLUSIONS: More than half of patients genotyped in the setting of CYP2C19-guided antiplatelet therapy received another medication impacted by CYP2C19 in the following year. Given that genotype is stable for a patient's lifetime, this finding has implications for cost effectiveness, patient care, and treatment outcomes beyond the indication for which it was originally performed.

Decrease in heart rate following the administration of sugammadex in adults.

BACKGROUND AND AIMS: Sugammadex is a novel agent for reversal of steroidal neuromuscular blocking agents (NMBAs) with potential advantages over acetylcholinesterase inhibitors. In preclinical trials, there have been rare instances of bradycardia with progression to cardiac arrest. To better define this issue, its incidence and mitigating factors, we prospectively evaluated the incidence of bradycardia after sugammadex administration in adults. MATERIAL AND METHODS: Patients ≥ 18 years of age who received sugammadex were included in this prospective, open label trial. After administration, heart rate (HR) was continuously monitored. HR was recorded every minute for 15 minutes and then every five minutes for the next 15 minutes or until patient was transferred out of the operating room. Bradycardia was defined as HR less than 60 beats/minute (bpm) or decrease in HR by ≥ 10 beats per minute (bpm) if the baseline HR was <70 bpm. RESULTS: The study cohort included 200 patients. Bradycardia was observed in 13 cases (7%; 95% confidence interval: 4, 11), occurring a median of 4 minutes after sugammadex administration (IQR: 4, 9, range: 2-25). Among patients developing bradycardia, two (15%) had cardiac comorbid conditions. One patient received treatment for bradycardia with ephedrine. No clinically significant blood pressure changes were noted. On bivariate analysis, patients receiving a higher initial sugammadex dose were more likely to develop bradycardia. On multivariable logistic regression, initial sugammadex dose was not associated with the risk of bradycardia. CONCLUSION: The incidence of bradycardia after administration of sugammadex in our study was low and not associated with significant hemodynamic changes.

Solvent Effects on the Stability and Delocalization of Aryl Dicyanomethyl Radicals: The Captodative Effect Revisited.

The captodative effect postulates that radicals substituted with both electron donating and accepting groups enjoy a special enhanced stabilization, a model given theoretical support by simple MO and resonance arguments. A key prediction from theory is that captodative stabilization of radicals is larger in polar solvents than in nonpolar solvents or the gas phase, which can be viewed in the resonance model as solvent stabilization of charge-separated resonance forms. Yet, several experimental studies have failed to observe a solvent effect on radical stability, casting doubt on key aspects of the captodative effect. Here, we examine in detail the effect of solvent on the stability of structurally related captodative aryl dicyanomethyl radicals. An attractive feature of these radicals is that they exist as stable steady state populations of radicals in equilibrium with their dimers, allowing us to directly characterize from experiment their thermodynamic stabilities and spin delocalization in solvents of varying polarity. In contrast to the prior studies, we find that captodative radicals are indeed stabilized by polar solvents, as measured by a shift in the radical-dimer association constants by up to 100-fold toward the radical upon going from nonpolar toluene to more polar DMF. Moreover, in polar solvents, the spin is shifted onto the donor substituent and away from the benzylic carbon. Within the resonance model, these results can be explained by the increased contributions of the zwitterionic resonance structures to the overall hybrid. These results provide experimental support to a key prediction from theory that had previously been dismissed.

Characterizing the Circulating Cell Populations in Traumatic Heterotopic Ossification.

Heterotopic ossification (HO) occurs secondary to trauma, causing pain and functional limitations. Identification of the cells that contribute to HO is critical to the development of therapies. Given that innate immune cells and mesenchymal stem cells are known contributors to HO, we sought to define the contribution of these populations to HO and to identify what, if any, contribution circulating populations have to HO. A shared circulation was obtained using a parabiosis model, established between an enhanced green fluorescent protein-positive/luciferase+ donor and a same-strain nonreporter recipient mouse. The nonreporter mouse received Achilles tendon transection and dorsal burn injury to induce HO formation. Bioluminescence imaging and immunostaining were performed to define the circulatory contribution of immune and mesenchymal cell populations. Histologic analysis showed circulating cells present throughout each stage of the developing HO anlagen. Circulating cells were present at the injury site during the inflammatory phase and proliferative period, with diminished contribution in mature HO. Immunostaining demonstrated that most early circulatory cells were from the innate immune system; only a small population of mesenchymal cells were present in the HO. We demonstrate the time course of the participation of circulatory cells in trauma-induced HO and identify populations of circulating cells present in different stages of HO. These findings further elucidate the relative contribution of local and systemic cell populations to HO.

Understanding the performance of a paper-based UV exposure sensor: The photodegradation mechanism of brilliant blue FCF in the presence of TiO2 photocatalysts in both the solid state and solution.

RATIONALE: The decolouration of brilliant blue FCF by the action of titanium dioxide (TiO2 ) under ultraviolet (UV) exposure has been recently reported as the basis of a paper-based sensor for monitoring UV sun exposure. The mechanism of brilliant blue FCF photodegradation in the presence of the photocatalyst and the resulting photoproducts are thus far unknown. METHODS: The UV-initiated photodegradation of brilliant blue FCF in the presence of TiO2 for both the aqueous and the solid state was investigated. Degradation in the solid state was observed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-MS). Decomposition of the dye in the aqueous state was analyzed using liquid chromatography/mass spectrometry (LC/MS) and ultraviolet-visible (UV-Vis) spectroscopy. RESULTS: After UV radiation exposure, the brilliant blue FCF base peak [M1 + NH4 ]+ (m/z calc. 766.194 found 766.194) decreased in the LC/MS chromatogram with a concomitant appearance of BB-FCF decomposition products involving the sequential loss of the N-ethyl and N-methylbenzene sulfonate (MBSA) groups, assigned as [M2 + H]+ (-MBSA, calc. 579.163 found 579.162), [M3 + H]+ (-MBSA, -Et, calc. 551.131 found 551.131), [M4 + H]+ (-2MBSA, calc. 409.158 found 409.158), [M5 + H]+ (-2MBSA, -Et, calc. 381.127 found 381.127). Ions [M2 + H]+ and [M3 + H]+ were also identified in the photodegradation products using MALDI-MS. Observation by UV-Vis indicated a decrease in the solution absorbance maxima and an associated blue-shift upon UV exposure in solution. CONCLUSIONS: The LC/MS analysis indicated two main oxidation processes. The most obvious was attack of the N-methylene, eliminating either ethyl or MBSA groups. The presence of the hydroxylated decomposition product M13 ([M13 + H]+ , calc. 595.157 found 595.157) supported this assignment. In addition, the detection of photoproduct M8, proposed to be 3-((ethylamino)methyl)benzenesulfonic acid ([M8 + H]+ , calc. 216.069 found 216.069), indicates an aryl-oxidative elimination. The absence of the aryl-hydroxy products normally expected to accompany the formation of M8 is proposed to be due to TiO2 -binding catechol-like derivatives, which are then removed upon filtration.

Systematic review of the impact of point-of-care testing for influenza on the outcomes of patients with acute respiratory tract infection.

Acute respiratory tract infections are a major cause of morbidity and mortality and represent a significant burden on the health care system. Laboratory testing is required to definitively distinguish infecting influenza virus from other pathogens, resulting in prolonged emergency department (ED) visits and unnecessary antibiotic use. Recently available rapid point-of-care tests (POCT) may allow for appropriate use of antiviral and antibiotic treatments and decrease patient lengths of stay. We undertook a systematic review to assess the effect of POCT for influenza on three outcomes: (1) antiviral prescription, (2) antibiotic prescription, and (3) patient length of stay in the ED. The databases Medline and Embase were searched using MeSH terms and keywords for influenza, POCT, antivirals, antibiotics, and length of stay. Amongst 245 studies screened, 30 were included. The majority of papers reporting on antiviral prescription found that a positive POCT result significantly increased use of antivirals for influenza compared with negative POCT results and standard supportive care. A positive POCT result also led to decreased antibiotic use. The results of studies assessing the effect of POCT on ED length of stay were not definitive. The studies assessed in this systematic review support the use of POCT for diagnosis of influenza in patients suffering an acute respiratory infection. Diagnosis using POCT may lead to more appropriate prescription of treatments for infectious agents. Further studies are needed to assess the effect of POCT on the length of stay in ED.

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification.

Pathologic extraskeletal bone formation, or heterotopic ossification (HO), occurs following mechanical trauma, burns, orthopedic operations, and in patients with hyperactivating mutations of the type I bone morphogenetic protein receptor ACVR1 (Activin type 1 receptor). Extraskeletal bone forms through an endochondral process with a cartilage intermediary prompting the hypothesis that hypoxic signaling present during cartilage formation drives HO development and that HO precursor cells derive from a mesenchymal lineage as defined by Paired related homeobox 1 (Prx). Here we demonstrate that Hypoxia inducible factor-1α (Hif1α), a key mediator of cellular adaptation to hypoxia, is highly expressed and active in three separate mouse models: trauma-induced, genetic, and a hybrid model of genetic and trauma-induced HO. In each of these models, Hif1α expression coincides with the expression of master transcription factor of cartilage, Sox9 [(sex determining region Y)-box 9]. Pharmacologic inhibition of Hif1α using PX-478 or rapamycin significantly decreased or inhibited extraskeletal bone formation. Importantly, de novo soft-tissue HO was eliminated or significantly diminished in treated mice. Lineage-tracing mice demonstrate that cells forming HO belong to the Prx lineage. Burn/tenotomy performed in lineage-specific Hif1α knockout mice (Prx-Cre/Hif1α(fl:fl)) resulted in substantially decreased HO, and again lack of de novo soft-tissue HO. Genetic loss of Hif1α in mesenchymal cells marked by Prx-cre prevents the formation of the mesenchymal condensations as shown by routine histology and immunostaining for Sox9 and PDGFRα. Pharmacologic inhibition of Hif1α had a similar effect on mesenchymal condensation development. Our findings indicate that Hif1α represents a promising target to prevent and treat pathologic extraskeletal bone.

Effect of Structure on the Spin-Spin Interactions of Tethered Dicyanomethyl Diradicals.

Stable organic radicals with switchable spin states have attracted attention for a variety of applications, but a fundamental understanding of how radical structure effects the weak bonding interactions between organic radicals is limited. To evaluate the effect of chemical structure on the strength and nature of such spin interactions, a series of 14 tethered aryl dicyanomethyl diradicals were synthesized, and the structure and thermodynamic properties of the diradicals were investigated. These studies indicate that the nature of the dimer and the equilibrium thermodynamic parameters of the diradical-dimer equilibria are highly sensitive to the attachment point of the linker, the length of the linker, and the substituents on the radical itself. Values of the intramolecular Ka vary from as small as 5 to as high as 105 depending on these variables. An X-ray crystal structure for a linked ortho-substituted diradical shows that the diradical forms an intramolecular sigma dimer in the crystalline state with an elongated C-C bond (1.637 Å). Subtle changes to the radical structure influences the nature of the spin interactions, as fixing the dimethylamino substituent on the radical into a ring to make a julolidine-derived diradical leads to the weakest bonding interaction observed (Δ Gbonding = 1 kcal mol-1) and changes the spin-paired species from a sigma dimer to a diradical pimer. This work has implications for the design of stimuli-responsive materials that can reversibly switch between the dramatically different properties of closed-shell species and the unique properties of diradicals.

Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon.

The pathologic development of heterotopic ossification (HO) is well described in patients with extensive trauma or with hyperactivating mutations of the bone morphogenetic protein (BMP) receptor ACVR1. However, identification of progenitor cells contributing to this process remains elusive. Here we show that connective tissue cells contribute to a substantial amount of HO anlagen caused by trauma using postnatal, tamoxifen-inducible, scleraxis-lineage restricted reporter mice (Scx-creERT2/tdTomatofl/fl ). When the scleraxis-lineage is restricted specifically to adults prior to injury marked cells contribute to each stage of the developing HO anlagen and coexpress markers of endochondral ossification (Osterix, SOX9). Furthermore, these adult preinjury restricted cells coexpressed mesenchymal stem cell markers including PDGFRα, Sca1, and S100A4 in HO. When constitutively active ACVR1 (caACVR1) was expressed in scx-cre cells in the absence of injury (Scx-cre/caACVR1fl/fl ), tendons and joints formed HO. Postnatal lineage-restricted, tamoxifen-inducible caACVR1 expression (Scx-creERT2/caACVR1fl/fl ) was sufficient to form HO after directed cardiotoxin-induced muscle injury. These findings suggest that cells expressing scleraxis within muscle or tendon contribute to HO in the setting of both trauma or hyperactive BMP receptor (e.g., caACVR1) activity. Stem Cells 2017;35:705-710.

Risk of peritoneal dialysis catheter-associated peritonitis following kidney transplant.

OBJECTIVE: Peritoneal dialysis (PD) patients have equivalent or slightly better kidney transplant outcomes when compared to hemodialysis (HD) patients. However, given the risk for postoperative infection, we sought to determine the risk factors for PD catheter-associated infections for patients who do not have the PD catheter removed at the time of engraftment. METHODS: Demographic and outcomes data were collected from 313 sequential PD patients who underwent kidney transplant from 2000 to 2015. Risk factors for postoperative peritonitis were analyzed using logistical regression. RESULTS: Of 329 patients with PD catheters at transplant, 16 PD catheters were removed at engraftment. Of the remaining 313 patients, 8.9% suffered post-transplant peritonitis. On univariate analysis, patients with peritonitis were significantly more likely to have used the PD catheter or HD within 6 weeks after transplant. Multivariate analysis had similar findings, with increased risk for those using the PD catheter after transplant, with a trend for those who underwent HD only within 6 weeks of transplant. CONCLUSION: These results suggest that delayed graft function requiring any type of dialysis is associated with increased post-transplant peritonitis risk.

Effect of Substituents on the Bond Strength of Air-Stable Dicyanomethyl Radical Thermochromes.

A series of substituted aryl dicyanomethyl radicals were synthesized, and the bonding thermodynamic parameters for self-dimerization were determined from van't Hoff plots obtained from variable-temperature electron paramagnetic resonance and ultraviolet-visible spectroscopy. At low temperatures, the radicals dimerize, but the colored, air-stable free radicals return upon heating. Heating and cooling cycles (5-95 °C) can be repeated without radical degradation and with striking thermochromic behavior. We find a linear free energy relationship between the Hammett para substituent parameter and the dimerization equilibrium constant, with para electron-donating substituents leading to a weaker bond and electron-withdrawing substituents leading to stronger bonds, following a captodative effect. Density functional theory investigations [B98D/6-31+G(d,p)] reveal that the dimers prefer a slip-stacked geometry and feature elongated bonds.

The Effects of 4'-Esterified Resveratrol Derivatives on Calcium Dynamics in Breast Cancer Cells.

Triple-negative breast cancer is a highly aggressive subtype of breast cancer. Frequently, breast cancer cells modulate their calcium signaling pathways to optimize growth. Unique calcium pathways in breast cancer cells could serve as a way to target tumorigenic cells without affecting normal tissue. Resveratrol has previously been shown to activate calcium signaling pathways. We use cell viability, single-cell calcium microscopy, and RT-PCR assays to determine the activity and mechanism of three different 4'-esterified resveratrol derivatives. We demonstrate that two of the derivatives reduce cell viability more effectively than resveratrol in MDA-MB-231 human breast cancer cells. The derivatives also activate similar pro-apoptotic calcium signaling pathways. In particular, the pivalated and butyrated resveratrol derivatives are intriguing putative chemotherapeutics because they are more effective at decreasing cell viability in vitro and inhibiting the plasma membrane Ca2+-ATPase, a protein that is often modulated in breast cancer.

Lymphatic Contribution to the Cellular Niche in Heterotopic Ossification.

OBJECTIVE: The objective of this study was to determine the contribution of lymphatic tissue to heterotopic ossification (HO). BACKGROUND: HO is the pathologic development of ectopic bone within soft tissues often following severe trauma. Characterization of the tissue niche supporting HO is critical to identifying therapies directed against this condition. Lymphangiogenesis is upregulated during incidents of trauma, thereby coincident with the niche supportive of HO. We hypothesized that lymphatic tissues play a critical role in HO formation. METHODS: Mice underwent hindlimb Achilles' tendon transection and dorsal burn injury (burn/tenotomy) to induce HO. The popliteal and inguinal lymph nodes were excised ipsilateral to the tenotomy site. Flow cytometry and immunostaining were used to quantify and localize lymphoendothelium. MicroCT was used to quantify HO. RESULTS: Enrichment of mature lymphatic tissues was noted 2 weeks after injury at the tendon transection sites when compared with the contralateral, intact tendon based on LYVE1+ tubules (10.9% vs 0.8%, P < 0.05). Excision of the inguinal and popliteal nodes with draining popliteal lymphatic vessel significantly decreased the presence of mature lymphoendothelium 2 weeks after injury (10.9% vs 3.3%, P < 0.05). Bone-cartilage-stromal progenitor cells (CD105+/AlphaV+/Tie2-/CD45-/CD90-/BP1-) were also significantly decreased after lymph node excision (10.2% vs 0.5%, P < 0.05). A significant decrease was noted in the volume of de novo HO present within the soft tissues (0.12 mm vs 0.02 mm). CONCLUSION: These findings suggest that lymphatic vessels are intimately linked with the de novo formation bone within soft tissues following trauma, and their presence may facilitate bone formation.