Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer.

The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1. While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities. Here, we use chemical proteomics to map druggable proteins that are selectively expressed in KEAP1-mutant NSCLC cells. Principal among these is NR0B1, an atypical orphan nuclear receptor that we show engages in a multimeric protein complex to regulate the transcriptional output of KEAP1-mutant NSCLC cells. We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain, and we demonstrate that these compounds disrupt NR0B1 complexes and impair the anchorage-independent growth of KEAP1-mutant cancer cells. Our findings designate NR0B1 as a druggable transcriptional regulator that supports NRF2-dependent lung cancers.

PGRMC2 is an intracellular haem chaperone critical for adipocyte function.

Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes1,2. The chemical reactivity of haem means that a network of intracellular chaperone proteins is required to avert the cytotoxic effects of free haem, but the constituents of such trafficking pathways are unknown3,4. Haem synthesis is completed in mitochondria, with ferrochelatase adding iron to protoporphyrin IX. How this vital but highly reactive metabolite is delivered from mitochondria to haemoproteins throughout the cell remains poorly defined3,4. Here we show that progesterone receptor membrane component 2 (PGRMC2) is required for delivery of labile, or signalling haem, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for haem, reduced labile haem in the nucleus and increased stability of the haem-responsive transcriptional repressors Rev-Erbα and BACH1. Ensuing alterations in gene expression caused severe mitochondrial defects that rendered adipose-specific PGRMC2-null mice unable to activate adaptive thermogenesis and prone to greater metabolic deterioration when fed a high-fat diet. By contrast, obese-diabetic mice treated with a small-molecule PGRMC2 activator showed substantial improvement of diabetic features. These studies uncover a role for PGRMC2 in intracellular haem transport, reveal the influence of adipose tissue haem dynamics on physiology and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.

Incidence and Outcomes of Cardiocerebral Infarction: A Cohort Study of 2 National Population-Based Registries.

BACKGROUND: Cardiocerebral infarction (CCI), which is concomitant with acute myocardial infarction (AMI) and acute ischemic stroke (AIS), is a rare but severe presentation. However, there are few data on CCI, and the treatment options are uncertain. We investigated the characteristics and outcomes of CCI compared with AMI or AIS alone. METHODS: We performed a retrospective cohort study of 120 531 patients with AMI and AIS from the national stroke and AMI registries in Singapore. Patients were categorized into AMI only, AIS only, synchronous CCI (same-day), and metachronous CCI (within 1 week). The primary outcome was all-cause mortality, and the secondary outcome was cardiovascular mortality. The mortality risks were compared using Cox regression. Multivariable models were adjusted for baseline demographics, clinical variables, and treatment for AMI or AIS. RESULTS: Of 127 919 patients identified, 120 531 (94.2%) were included; 74 219 (61.6%) patients had AMI only, 44 721 (37.1%) had AIS only, 625 (0.5%) had synchronous CCI, and 966 (0.8%) had metachronous CCI. The mean age was 67.7 (SD, 14.0) years. Synchronous and metachronous CCI had a higher risk of 30-day mortality (synchronous: adjusted HR [aHR], 2.41 [95% CI, 1.77-3.28]; metachronous: aHR, 2.80 [95% CI, 2.11-3.73]) than AMI only and AIS only (synchronous: aHR, 2.90 [95% CI, 1.87-4.51]; metachronous: aHR, 4.36 [95% CI, 3.03-6.27]). The risk of cardiovascular mortality was higher in synchronous and metachronous CCI than AMI (synchronous: aHR, 3.03 [95% CI, 2.15-4.28]; metachronous: aHR, 3.41 [95% CI, 2.50-4.65]) or AIS only (synchronous: aHR, 2.58 [95% CI, 1.52-4.36]; metachronous: aHR, 4.52 [95% CI, 2.95-6.92]). In synchronous CCI, AMI was less likely to be managed with PCI and secondary prevention medications (P<0.001) compared with AMI only. CONCLUSIONS: Synchronous CCI occurred in 1 in 200 cases of AIS and AMI. Synchronous and metachronous CCI had higher mortality than AMI or AIS alone.

Cholic Acid/Glutathione-Assembled Nanofibrils for Stabilizing Pickering Emulsion Biogels.

Achieving the delicate balance required for both emulsion and gel characteristics, while also imparting biological functionality in gelled emulsions, poses a significant challenge. Herein, Pickering emulsion biogels stabilized is reported by novel biological nanofibrils assembled from natural glutathione (GSH) and a tripod cholic acid derivative (TCA) via electrostatic interactions. GSH, composed of tripeptides with carboxyl groups, facilitates the protonation and dissolution of TCA compounds in water and the electrostatic interactions between GSH and TCA trigger nanofibrillar assembly. Fibrous nuclei initially emerge, and the formed mature nanofibrils can generate a stable hydrogel at a low solid concentration. These nanofibrils exhibit efficient emulsifying capability, enabling the preparation of stable Pickering oil-in-water (O/W) emulsion gels with adjustable phase volume ratios. The entangled nanofibrils adsorbed at the oil-water interface restrict droplet movement, imparting viscoelasticity and injectability to the emulsions. Remarkably, the biocompatible nanofibrils and stabilized emulsion gels demonstrate promising scavenging properties against reactive oxygen species (ROS). This strategy may open new scenarios for the design of advanced emulsion gel materials using natural precursors and affordable building blocks for biomedical applications.

Lenacapavir Exhibits Atropisomerism-Mechanistic Pharmacokinetics and Disposition Studies of Lenacapavir Reveal Intestinal Excretion as a Major Clearance Pathway.

Lenacapavir (LEN), a long-acting injectable, is the first approved human immunodeficiency virus type 1 capsid inhibitor and one of a few Food and Drug Administration-approved drugs that exhibit atropisomerism. LEN exists as a mixture of two class 2 atropisomers that interconvert at a fast rate (half-life < 2 hours) with a ratio that is stable over time and unaffected by enzymes or binding to proteins in plasma. LEN exhibits low systemic clearance (CL) in nonclinical species and humans; however, in all species, the observed CL was higher than the in vitro predicted CL. The volume of distribution was moderate in nonclinical species and consistent with the tissue distribution observed by whole-body autoradiography in rats. LEN does not distribute to brain, consistent with being a P-glycoprotein (P-gp) substrate. Mechanistic drug disposition studies with [14C]LEN in intravenously dosed bile duct-cannulated rats and dogs showed a substantial amount of unchanged LEN (31%-60% of dose) excreted in feces, indicating that intestinal excretion (IE) was a major clearance pathway for LEN in both species. Coadministration of oral elacridar, a P-gp inhibitor, in rats decreased CL and IE of LEN. Renal excretion was < 1% of dose in both species. In plasma, almost all radioactivity was unchanged LEN. Low levels of metabolites in excreta included LEN conjugates with glutathione, pentose, and glucuronic acid, which were consistent with metabolites formed in vitro in Hµrel hepatocyte cocultures and those observed in human. Our studies highlight the importance of IE for efflux substrates that are highly metabolically stable compounds with slow elimination rates. SIGNIFICANCE STATEMENT: LEN is a long-acting injectable that exists as conformationally stable atropisomers. Due to an atropisomeric interconversion rate that significantly exceeds the in vivo elimination rate, the atropisomer ratio of LEN remains constant in circulation. The disposition of LEN highlights that intestinal excretion has a substantial part in the elimination of compounds that are metabolically highly stable and efflux transporter substrates.

Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3- and viral-induced expression of type I interferons.

Toll-like receptors (TLRs) sense pathogen-associated molecules and respond by inducing cytokines and type I interferon. Here we show that genetic ablation of the E3 ubiquitin ligase Pellino3 augmented the expression of type I interferon but not of proinflammatory cytokines in response to TLR3 activation. Pellino3-deficient mice had greater resistance against the pathogenic and lethal effects of encephalomyocarditis virus (EMCV). TLR3 signaling induced Pellino3, which in turn interacted with and ubiquitinated TRAF6. This modification suppressed the ability of TRAF6 to interact with and activate IRF7, resulting in downregulation of type I interferon expression. Our findings highlight a new physiological role for Pellino3 and define a new autoregulatory network for controlling type I interferon expression.

Assessing Pleiotropic Effects of a Mixed-Mode Perpetrator Drug, Rifampicin, by Multiple Endogenous Biomarkers in Dogs.

Rifampicin (RIF) is a mixed-mode perpetrator that produces pleiotropic effects on liver cytochrome P450 enzymes and drug transporters. To assess the complex drug-drug interaction liabilities of RIF in vivo, a known probe substrate, midazolam (MDZ), along with multiple endogenous biomarkers were simultaneously monitored in beagle dogs before and after a 7-day treatment period by RIF at 20 mg/kg per day. Confirmed by the reduced MDZ plasma exposure and elevated 4ß-hydroxycholesterol (4ß-HC, biomarker of CYP3A activities) level, CYP3A was significantly induced after repeated RIF doses, and such induction persisted for 3 days after cessation of the RIF administration. On the other hand, increased plasma levels of coproporphyrin (CP)-I and III [biomarkers of organic anion transporting polypeptides 1b (Oatp1b) activities] were observed after the first dose of RIF. Plasma CPs started to decline as RIF exposure decreased, and they returned to baseline 3 days after cessation of the RIF administration. The data suggested the acute (inhibitory) and chronic (inductive) effects of RIF on Oatp1b and CYP3A enzymes, respectively, and a 3-day washout period is deemed adequate to remove superimposed Oatp1b inhibition from CYP3A induction. In addition, apparent self-induction of RIF was observed as its terminal half-life was significantly altered after multiple doses. Overall, our investigation illustrated the need for appropriate timing of modulator dosing to differentiate between transporter inhibition and enzyme induction. As further indicated by the CP data, induction of Oatp1b activities was not likely after repeated RIF administration. SIGNIFICANCE STATEMENT: This investigation demonstrated the utility of endogenous biomarkers towards complex drug-drug interactions by rifampicin (RIF) and successfully determined the optimal timing to differentiate between transporter inhibition and enzyme induction. Based on experimental evidence, Oatp1b induction following repeated RIF administration was unlikely, and apparent self-induction of RIF elimination was observed.

Prehospital transfusion of labile blood product using intraosseous perfusion with multi-lumen extender: Why not?

BACKGROUND: French prehospital military medical teams are provided with labile blood products to effectively address hemorrhagic shock. In combat environment, standard good medical practice may limit efficacy of therapeutic goals regarding damage control resuscitation. STUDY DESIGN AND METHODS: We present here a case report describing the management of a soldier heavily wounded during a helicopter forward medical evacuation in Sahel region. RESULTS: We report the challenge encountered by medical team using only a humeral intraosseous route available due to severity of lesions and challenging environment. In this configuration, multi-lumen extender enabled transfusion of two units of packed red blood cells and two units of plasma, and analgesia while limiting manipulation and dislodgment of the fragile intraosseous route. This situation, outside of usual good medical practice, raises issues of hemolysis, physicochemical compability of drugs and blood products, and consequences on flow rate reduction. DISCUSSION: With this case, we emphasize the benefit of multi-lumen extender associated with intraosseous route for early management of heavy casualties in harsh prehospital environment. Literature suggests that hemolysis and physicochemical compability should remain limited. The main issue of this setting consists of flow reduction and can be addressed by prioritizing humeral route, and using counter pressure cuffs, until a second peripheral or central line is available and management can resume without the need for multi-lumen extender.

Bleeding and thrombotic risk of different antiplatelet regimens posttranscatheter edge-to-edge mitral valve repair in patients with an indication for oral anticoagulation: Results from an all-comers national registry.

BACKGROUND: Evidence-based recommendations for antithrombotic treatment in patients who have an indication for oral anticoagulation (OAC) after transcatheter edge-to-edge mitral valve repair (TEER) are lacking. AIMS: To compare bleeding and thrombotic risk for different antithrombotic regimens post-TEER with MitraClip in an unselected population with the need for OACs. METHODS: Bleeding and thrombotic complications (stroke and myocardial infarction) up to 3 months after TEER with mitraclip were evaluated in 322 consecutive pts with an indication for OACs. These endpoints were defined by the Mitral Valve Academic Research Consortium criteria and were compared between two antithrombotic regimens: single antithrombotic therapy with OAC (single ATT) and double/triple ATT with a combination of OAC and aspirin and/or clopidogrel (combined ATT). RESULTS: Collectively, 108 (34%) patients received single ATT, 203 (63%) received double ATT and 11 (3%) received triple ATT. Bleeding events occurred in 67 patients (20.9%), with access site related events being the most frequent cause (37%). Bleeding complications were observed more frequently in the combined ATT group than in the single ATT group: 24% versus 14% [p = 0.03, adjusted RR: 0.55 (0.3-0.98)]. Within the combined group, the bleeding risk was 23% in the double ATT and 45% in the triple ATT group. Thrombotic complications occurred in only three patients (0.9%), and all belonged to the combined ATT group. CONCLUSIONS: In patients with an indication for OACs, withholding of antiplatelet therapy post-TEER with Mitraclip was associated with a 45% reduction in bleeding and without a signal of increased thrombotic risk.

Ontogeny of Human Liver Aldehyde Oxidase: Developmental Changes and Implications for Drug Metabolism.

Despite the increasing importance of aldehyde oxidase (AO) in the drug metabolism of clinical candidates, ontogeny data for AO are limited. The objective of our study was to characterize the age-dependent AO content and activity in the human liver cytosolic fraction (HLC) and human hepatocytes (HH). HLC (n = 121 donors) and HH (n = 50 donors) were analyzed for (1) AO protein content by quantitative proteomics and (2) enzyme activity using carbazeran as a probe substrate. AO activity showed high technical variability and poor correlation with the content in HLC samples, whereas hepatocyte samples showed a strong correlation between the content and activity. Similarly, AO content and activity showed no significant age-dependent differences in HLC samples, whereas the average AO content and activity in hepatocytes increased significantly (∼20-40-fold) from the neonatal levels (0-28 days). Based on the hepatocyte data, the age at which 50% of the adult AO content is reached (age50) was 3.15 years (0.32-13.97 years, 95% CI). Metabolite profiling of carbazeran revealed age-dependent metabolic switching and the role of non-AO mechanisms (glucuronidation and desmethylation) in carbazeran elimination. The content-activity correlation in hepatocytes improved significantly (R2 = 0.95; p < 0.0001) in samples showing <10% contribution of glucuronidation toward the overall metabolism, confirming that AO-mediated oxidation and glucuronidation are the key routes of carbazeran metabolism. Considering the confounding effect of glucuronidation on AO activity, AO content-based ontogeny data are a more direct reflection of developmental changes in protein expression. The comprehensive ontogeny data of AO in HH samples are more reliable than HLC data, which are important for developing robust physiologically based pharmacokinetic models for predicting AO-mediated metabolism in children.

Consensus-Driven Recommendations to Support Physician Pregnancy, Adoption, Surrogacy, Parental Leave, and Lactation in Emergency Medicine.

The emergency department clinical environment is unique, and guidelines for promoting supportive and equitable workplace cultures ensure success and longevity for pregnant persons and parents in emergency medicine. There is paucity, variability, and dissatisfaction with current parental (historically referred to as maternity and paternity) leave policies. This paper describes the development of consensus-derived recommendations to serve as a framework for emergency departments across the country for incorporating family-friendly policies. Policies that foster a family-inclusive workplace by allowing for professional advancement without sacrificing personal values regardless of sex, gender, and gender identity are critical for emergency medicine recruitment and retention.

Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects.

Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than ß-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.

Lower Perceived Social Support During Hospitalization by Close Family Members may have Significant Associations with Psychological Distress 1 Month After Cardiac Arrest.

BACKGROUND: The perception of having poor social support is associated with worse symptoms of psychological distress in close family members of critically ill patients, yet this has never been tested after cardiac arrest. METHODS: Close family members of consecutive patients with cardiac arrest hospitalized at an academic tertiary care center participated in a prospective study. The validated Multidimensional Scale of Perceived Social Support (MSPSS) cued to index hospitalization was administered before discharge. Multivariate linear regressions estimated the associations between the total MSPSS score and total scores on the Patient Health Questionnaire-8 (PHQ-8), Generalized Anxiety Disorder 2-item (GAD-2), and the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), assessed 1 month after cardiac arrest. RESULTS: In 102 participants (mean age 52 ± 15 years, 70% female, 21% Black, 33% Hispanic) with complete data, the prevalence of depression, generalized anxiety, and probable posttraumatic stress disorder at a median duration of 28.5 days (interquartile range 10-63 days) from cardiac arrest was 61%, 34%, and 13%, respectively. A lower MSPSS score was significantly associated with higher PHQ-8 scores (ß = - 0.11 [95% confidence interval - 0.04 to - 0.18]; p < 0.01), even after adjusting for family members' age, sex, prior psychiatric condition, and witnessing of cardiopulmonary resuscitation and patient's discharge disposition (ß = - 0.11 [95% confidence interval - 0.02 to - 0.15]; p < 0.01). Similarly, significant inverse associations of total MSPSS scores were seen with 1-month GAD-2 and PCL-5 scores. CONCLUSIONS: Poor social support during hospitalization, as perceived by close family members of cardiac arrest survivors, is associated with worse depressive symptoms at 1 month. Temporal changes in social networks and psychological distress warrant further investigation.

Residual Humoral Immunity Sustained Over Decades in a Cohort of Vaccinia-Vaccinated Individuals.

Serological testing of Singaporeans who received childhood smallpox vaccination found anti-vaccinia IgG binding and neutralizing activity indicating long-term humoral immunity. There was correlation between IgG and neutralizing titers indicating IgG could be used as a surrogate marker for humoral immunity. In 2019, Singapore experienced a case of imported monkeypox. As with smallpox, disease can be prevented through vaccination, which was mandatory for Singaporean infants until 1981. However, the degree of residual immunity in older vaccinated Singaporeans remains unknown. Sera from individuals born 1946-1984 were therefore tested and those born prior to 1981 were found to have higher anti-vaccinia IgG and neutralizing activity titers. This suggests that protective humoral immunity remains, which could reduce disease severity in an orthopoxvirus outbreak. Correlation between IgG and neutralizing titers was observed indicating that serology could be used as a surrogate marker for immunity.

Nonlinear Changes in Facial Affect and Posttraumatic Growth: Assessment of Ecological Momentary Assessment Video Data.

Posttraumatic Growth (PTG), characterized by newfound meaning, perspective, and purpose for trauma survivors, remains enigmatic in its nature. This state is thought to arise from the dynamic interplay of biopsychosocial factors; however, the nature of this interplay is unclear. This study aimed to investigate the intricate relationship between PTG and facial affect dynamics, shedding light on the complex interplay of biopsychosocial factors that underpin this transformative process. We conducted a comprehensive investigation involving 19 wildfire survivors who provided daily self-reported PTG ratings alongside smartphone videos analyzed using Automated Facial Affect Recognition (AFAR) software. Our findings revealed compelling evidence of self-organization within facial affect, as indicated by notably high mean R2 and shape parameter values (i.e., nonlinear indices indicative of structural integrity and flexibility). Further regression analyses unveiled a significant interaction between the degree of facial affect 'burstiness' and coping self-efficacy (CSE) on PTG. This interaction suggested that PTG development was a nuanced process intricately linked to the coherence of emotion patterns exhibited by individuals. These insights illuminate the multifaceted dynamics at play in the emergence of PTG and contribute to a broader understanding of its biopsychosocial foundations.

Light-Driven Spatiotemporal Pickering Emulsion Droplet Manipulation Enabled by Plasmonic Hybrid Microgels.

The past decades have witnessed the development of various stimuli-responsive materials with tailored functionalities, enabling droplet manipulation through external force fields. Among different strategies, light exhibits excellent flexibility for contactless control of droplets, particularly in three-dimensional space. Here, we present a facile synthesis of plasmonic hybrid microgels based on the electrostatic heterocoagulation between cationic microgels and anionic Au nanoparticles. The hybrid microgels are effective stabilizers of oil-in-water Pickering emulsions. In addition, the laser irradiation on Au nanoparticles creats a "cascade effect" to thermally responsive microgels, which triggers a change in microgel wettability, resulting in microgel desorption and emulsion destabilization. More importantly, the localized heating generated by a focused laser induces the generation of a vapor bubble inside oil droplets, leading to the formation of a novel air-in-oil-in-water (A/O/W) emulsion. These A/O/W droplets are able to mimic natural microswimmers in an aqueous environment by tracking the motion of a laser spot, thus achieving on-demand droplet merging and chemical communication between isolated droplets. Such proposed systems are expected to extend the applications of microgel-stabilized Pickering emulsions for substance transport, programmed release and controlled catalytic reactions.

Dissecting Parameters Contributing to the Underprediction of Aldehyde Oxidase-Mediated Metabolic Clearance of Drugs.

We investigated the effect of variability and instability in aldehyde oxidase (AO) content and activity on the scaling of in vitro metabolism data. AO content and activity in human liver cytosol (HLC) and five recombinant human AO preparations (rAO) were determined using targeted proteomics and carbazeran oxidation assay, respectively. AO content was highly variable as indicated by the relative expression factor (REF; i.e., HLC to rAO content) ranging from 0.001 to 1.7 across different in vitro systems. The activity of AO in HLC degrades at a 10-fold higher rate in the presence of the substrate as compared with the activity performed after preincubation without substrate. To scale the metabolic activity from rAO to HLC, a protein-normalized activity factor (pnAF) was proposed wherein the activity was corrected by AO content, which revealed up to sixfold higher AO activity in HLC versus rAO systems. A similar value of pnAF was observed for another substrate, ripasudil. Physiologically based pharmacokinetic (PBPK) modeling revealed a significant additional clearance (CL; 66%), which allowed for the successful prediction of in vivo CL of four other substrates, i.e., O-benzyl guanine, BIBX1382, zaleplon, and zoniporide. For carbazeran, the metabolite identification study showed that the direct glucuronidation may be contributing to around 12% elimination. Taken together, this study identified differential protein content, instability of in vitro activity, role of additional AO clearance, and unaccounted metabolic pathways as plausible reasons for the underprediction of AO-mediated drug metabolism. Consideration of these factors and integration of REF and pnAF in PBPK models will allow better prediction of AO metabolism. SIGNIFICANCE STATEMENT: This study elucidated the plausible reasons for the underprediction of aldehyde oxidase (AO)-mediated drug metabolism and provided recommendations to address them. It demonstrated that integrating protein content and activity differences and accounting for the loss of AO activity, as well as consideration of extrahepatic clearance and additional pathways, would improve the in vitro to in vivo extrapolation of AO-mediated drug metabolism using physiologically based pharmacokinetic modeling.

Impact of Native Language, English Proficiency, and Language Concordance on Interpersonal Care During Evaluation of Acute Coronary Syndrome.

BACKGROUND: High-quality interpersonal interactions between clinicians and patients can improve communication and reduce health disparities among patients with novice English proficiency (NEP). Yet, little is known about the impact of native language, NEP, and native language concordance on patient on perceptions of interpersonal care in the emergency department (ED). OBJECTIVE: To determine the associations of native language, NEP, and native language concordance with patient perceptions of interpersonal care among patients undergoing evaluation for suspected acute coronary syndrome (ACS) in the ED. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 1000 patients undergoing evaluation for suspected ACS at an urban ED from 2013 to 2016. MAIN MEASURES: English- and Spanish-speaking patients were surveyed to identify native language, English proficiency (classified as advanced, intermediate, or novice), and perceived language of the treating ED clinician. Patient perceptions of interpersonal care were assessed using the Interpersonal Processes of Care (IPC) survey, a validated 18-item tool for assessing social-psychological domains of patient-clinician interactions. IPC scores ≤ 4 were categorized as sub-optimal (range, 1-5). The associations between native language, English proficiency, and native language concordance with sub-optimal communication were assessed using hierarchical logistic regression adjusted for all three language variables, sociodemographic characteristics, and depression. KEY RESULTS: Nine hundred thirty-three patients (48.0% native non-English-speaking, 55.7% Hispanic) completed the IPC; 522 (57.4%) perceived native language concordance. In unadjusted analyses, non-English native language (OR 1.38, 95% CI 1.04-1.82) and NEP (OR 1.45, 95% CI 1.06-1.98) were associated with sub-optimal communication, whereas language concordance was protective (OR 0.61, 95% CI 0.46-0.81). In fully adjusted analyses, only language concordance remained significantly associated with sub-optimal communication (AOR 0.62, 95% CI 0.42-0.93). CONCLUSIONS: This study suggests that perceived native language concordance acts as a protective factor for patient-clinician interpersonal care in the acute setting, regardless of native language or English proficiency.

Universality of Scaling Laws Governing Contact and Spreading Time Spans of Bouncing Liquid Marbles and its Physical Origin.

The impact of liquid marbles coated with a diversity of hydrophobic powders with various solid substrates, including hydrophobic, hydrophilic, and superhydrophobic ones, was investigated. The contact time of the bouncing marbles was studied. Universal scaling behavior of the contact time tc as a function of the Weber number (We) was established; the scaling law tc = tc(We) was independent of the kind of powder and the type of solid substrate. The total contact time consists of spreading time and retraction time. It is weakly dependent on We and this is true for all kinds of studied powders and substrates. This observation hints to the surface tension/inertia spring model governing the impact. By contrast, the spreading time ts scales as [Formula: see text], n = 0.28 - 0.30 ± 0.002. We relate the origin of this scaling law to the viscous dissipation occurring within the spreading marbles. The retraction time tr grows weakly with the Weber number. The scaling law was changed at threshold values of We ≅ 15-20. It is reasonable to explain this change with the breaking of the Leidenfrost regime of spreading under high values of We.

Phase Inversion of Pickering Emulsions Induced by Interfacial Electrostatic Attraction.

Phase inversion of Pickering emulsions from water-in-oil (W/O) to oil-in-water (O/W) is achieved by the formation of an interfacial particle bilayer using negatively charged and positively charged particles dispersed in water and oil, respectively, before emulsification. A mechanism based on electrostatic attraction across the toluene-water interface is proposed and verified by systematic investigation of the parameters that affect the surface charge of negatively charged particles such as pH and salt concentration. Cationic silica-FITC particles (600 nm) can be dispersed in toluene and stabilize W/O emulsions alone; phase inversion of this emulsion can be induced by the addition of anionic silica-RB particles in the aqueous phase at a concentration of 1.0 wt % or above. It is revealed that silica-RB particles of a smaller size (100 nm) can induce emulsion phase inversion at a much lower concentration (0.4 wt %) and an interfacial particle bilayer is clearly revealed by CLSM and SEM images. By tuning the surface charge density of silica-RB particles, the electrostatic attraction mechanism leading to the formation of the interfacial particle bilayer is confirmed and emulsion stability can be tuned as demonstrated by osmotic pressure enhancement results obtained from centrifugation.