Comparison of Chemotherapeutic Activities of Rhodamine-Based GUMBOS and NanoGUMBOS.

Rhodamine derivatives have been widely investigated for their mitochondrial targeting and chemotherapeutic properties that result from their lipophilic cationic structures. In previous research, we have found that conversion of Rhodamine 6G into nanoGUMBOS, i.e., nanomaterials derived from a group of uniform materials based on organic salts (GUMBOS), led to selective chemotherapeutic toxicity for cancer cells over normal cells. Herein, we investigate the chemotherapeutic activity of GUMBOS derived from four different rhodamine derivatives, two bearing an ester group, i.e., Rhodamine 123 (R123) and SNAFR-5, and two bearing a carboxylic acid group, i.e., rhodamine 110 (R110) and rhodamine B (RB). In this study, we evaluate (1) relative hydrophobicity via octanol-water partition coefficients, (2) cytotoxicity, and (3) cellular uptake in order to evaluate possible structure-activity relationships between these different compounds. Intriguingly, we found that while GUMBOS derived from R123 and SNAFR-5 formed nanoGUMBOS in aqueous medium, no distinct nanoparticles are observed for RB and R110 GUMBOS. Further investigation revealed that the relatively high water solubility of R110 and RB GUMBOS hinders nanoparticle formation. Subsequently, while R123 and SNAFR-5 displayed selective chemotherapeutic toxicity similar to that of previously investigated R6G nanoGUMBOS, the R110 and RB GUMBOS were lacking in this property. Additionally, the chemotherapeutic toxicities of R123 and SNAFR-5 nanoGUMBOS were also significantly greater than R110 and RB GUMBOS. Observed results were consistent with decreased cellular uptake of R110 and RB as compared to R123 and SNAFR-5 compounds. Moreover, these results are also consistent with previous observations that suggest that nanoparticle formation is critical to the observed selective chemotherapeutic properties as well as the chemotherapeutic efficacy of rhodamine nanoGUMBOS.

Endocytic Selective Toxicity of Rhodamine 6G nanoGUMBOS in Breast Cancer Cells.

Herein, we report on the role of endocytosis in the selective chemotherpeutic toxicity of rhodamine 6G (R6G) based nanomaterials, i.e., nanoGUMBOS, that are derived from a group of uniform materials based on organic salts (GUMBOS). Evaluation of cellular uptake in the presence and absence of endocytosis inhibitors suggests nanoGUMBOS internalization via clathrin-mediated endocytosis in cancer cells and reveals lack of endocytic internalization in normal cells. Results from characterization of these nanomaterials suggest that endocytic internalization in cancer cells leads to nanoGUMBOS dissociation within the endosomal environment. This ultimately results in selective cytotoxicity of the nanoGUMBOS for cancer cells with no toxicity toward normal cells under examined conditions. Following examination of the selectivity mechanism, in vivo investigations were performed to examine potential therapeutic properties of these nanoparticles. Remarkably, nanoGUMBOS treatment using a mouse xenograft model reduced the tumor volume by 50% suggesting retention of in vitro therapeutic properties in vivo. These results corroborate the selective behavior of nanoGUMBOS and demonstrate their in vivo therapeutic effects, providing further insight into the possible use of these nanomaterials as potential chemotherapeutic agents.

Tunable cytotoxicity of rhodamine 6G via anion variations.

Chemotherapeutic agents with low toxicity to normal tissues are a major goal in cancer research. In this regard, the therapeutic activities of cationic dyes, such as rhodamine 6G, toward cancer cells have been studied for decades with observed toxicities toward normal and cancer cells. Herein, we report rhodamine 6G-based organic salts with varying counteranions that are stable under physiological conditions, display excellent fluorescence photostability, and more importantly have tunable chemotherapeutic properties. Our in vitro studies indicate that the hydrophobic compounds of this series allow production of nanoparticles which are nontoxic to normal cells and toxic to cancer cells. Furthermore, the anions, in combination with cations such as sodium, were observed to be nontoxic to both normal and cancer cells. To the best of our knowledge, this is the first demonstration that both the cation and anion play an extremely important and cooperative role in the antitumor properties of these compounds.

Virtual Peer Teaching During the COVID-19 Pandemic.

Virtual peer teaching can be part of the solution to challenges in medical education during the pandemic. We developed an online clinician teacher elective, implemented virtual peer teaching throughout our curriculum, and believe it benefits students, peer teachers, and faculty. We plan to continue virtual peer teaching beyond the pandemic.

Teaching Medical Students Skills for Effective Communication With Patients Who Have Communication Disorders.

Purpose Patients with communication impairments including speech, language, cognition, or hearing disorders face many barriers to communication in health care settings. These patients report loss of autonomy in health care decision making, are at increased risk for medical errors, and are less satisfied with health care than patients without communication disorders. Although medical students receive training in effective patient-provider communication, most of this training assumes patients have intact communication abilities. Medical students and other health care providers are often unprepared to meet the communication needs of patients with communication disorders in health care encounters. The purpose of this study was to assess the impact of a curriculum for training medical students to communicate effectively with patients who have a range of communication disorders. Method Twenty-six 2nd-year medical students volunteered for assessments before and after a required workshop in a class. This workshop included instruction about different types of communication disorders and communication strategies, followed by practice with standardized patients portraying different communication disorders. Outcome measures included a knowledge test, ratings of self-efficacy, and evaluation of students' skills when interviewing standardized patients portraying aphasia and dysarthria. Results Medical students demonstrated significant improvements in knowledge, self-efficacy, and use of recommended communication techniques. Conclusions The curriculum appeared effective in changing medical students' knowledge and skills for working with patients with communication disorders. Equipping medical students to meet the needs of patients with communication disorders is 1 key element for improving the quality of health care for this patient population.

Tumor-Targeting NIRF NanoGUMBOS with Cyclodextrin-Enhanced Chemo/Photothermal Antitumor Activities.

The near-infrared fluorescent (NIRF) dye, IR780, is recognized as a promising theranostic agent and has been widely investigated for imaging, chemotherapeutic, and phototherapeutic applications. However, its poor photostability and nonselective toxicities toward both cancer and normal cells limit its biological applications. Herein, we introduce the use of GUMBOS (a group of uniform materials based on organic salts) developed through counter-anion exchange with IR780 and subsequent nanomaterials (nanoGUMBOS) formed by complexation with cyclodextrin (CD) for enhanced chemo/photothermal therapy. Such CD-based nanoGUMBOS display improved aqueous stability, photostability, and photothermal effects relative to traditional IR780. The examination of in vitro cytotoxicity reveals that CD-based nanoGUMBOS are selectively toxic toward cancer cells and exhibit synergistically enhanced cytotoxicity toward cancer cells upon NIR laser irradiation. Additionally, in vivo NIRF imaging demonstrated selective accumulation of these nanoGUMBOS within the tumor site, indicating tumor-targeting properties. Further in vivo therapeutic study of these CD-based nanoGUMBOS suggests excellent chemo/photothermal antitumor effects. Using these studies, we herein demonstrate a promising strategy, via conversion of IR780 into nanoGUMBOS, that can be used for improved theranostic cancer treatment.

Severe drug hypersensitivity reaction in a young woman treated with doxycycline.

Doxycycline is a commonly prescribed medication for the management of acne vulgaris. Severe adverse reactions to this medication are uncommon. We describe an unusual case of a 20-year-old female who experienced a life-threatening hypersensitivity reaction, including fever, lymphadenopathy, hepatitis, nephritis and severe pneumonitis with respiratory failure following oral administration of doxycycline for facial acne.

Mitochondria targeting IR780-based nanoGUMBOS for enhanced selective toxicity towards cancer cells.

Herein, a simple counter-ion variation strategy is proposed and demonstrated for design of an array of near infrared IR780-based nanoGUMBOS (nanomaterials from a Group of Uniform Materials Based on Organic Salts) to produce enhanced anticancer activity. These nanomaterials were synthesized by direct nanoengineering of IR780-based GUMBOS using a reprecipitation method, without addition of any other materials. Thus, these novel nanomaterials can serve as carrier-free nanodrugs, providing several distinct advantages over conventional chemotherapeutics. Examination of the size and stability of these nanoGUMBOS indicates formation of approximately 100 nm nanoparticles that are stable under biological conditions. Interestingly, in vitro chemotherapeutic applications of these nanoGUMBOS indicate two to four-fold enhanced toxicity towards breast cancer cells as compared to the parent dye, while still maintaining minimal toxicity towards normal cells. The mechanism of cancer toxicity for these nanoGUMBOS was also examined by a study of their sub-cellular localization as well as using a mitochondrial toxicity assay. Analyses of data from these studies revealed that all nanoGUMBOS primarily accumulate in the mitochondria of cancer cells and produce dysfunction in the mitochondria to induce cell death. Using these studies, we demonstrate tunable properties of IR780-based nanoGUMBOS through simple variation of counter-ions, thus providing a promising strategy for future design of better nanomedicines to be used for cancer therapy.

Enhanced chemotherapeutic toxicity of cyclodextrin templated size-tunable rhodamine 6G nanoGUMBOS.

Nanodrugs have been widely investigated for combating the large number of side effects associated with conventional therapeutics. Several investigations of such nanomedicines have demonstrated the profound role of nanoparticle size in therapeutic efficacy. Herein, we report the role of cyclodextrin (CD)-templating on the size and therapeutic properties of rhodamine 6G (R6G) nanoGUMBOS, i.e. nanomaterials derived from a Group of Uniform Materials Based on Organic Salts (GUMBOS). In these studies, templating of nanoGUMBOS using 2-hydroxypropyl-alpha (2-HP-α), 2-hydroxypropyl beta (2-HP-ß), and gamma (γ) cyclodextrin (CD) led to a significant reduction in size and enhanced uniformity as indicated by transmission electron microscopy (TEM) images. In addition, CD-templated nanoGUMBOS remarkably displayed a three to four fold enhancement in toxicity towards cancer cells as compared to nanoGUMBOS without CD-templates, suggesting a significant improvement in therapeutic efficacy. Correlation between size and toxicity suggests that CD-templated nanoparticles of ∼70 to 80 nm produced optimal toxicity. Even more interesting, all investigated nanoGUMBOS displayed no toxicity toward normal cells under examined conditions. Moreover, these nanoGUMBOS display comparable chemotherapeutic toxicity to the parent dye, [R6G][Cl], while also eliminating toxicity towards normal cells, indicating their strong chemotherapeutic potential. The studies outlined here provide further insight into an approach that may be employed for rapid synthesis of size tunable nanodrugs for enhanced chemotherapeutic efficacy.

Interprofessional Error Disclosure Training for Medical, Nursing, Pharmacy, Dental, and Physician Assistant Students.

INTRODUCTION: Errors that harm patients often have many contributing factors and ideally should be disclosed by a team rather than an individual provider. However, most health professions students learn about errors and error disclosure in a single-profession class. METHODS: We developed a 2-hour small-group session in which our students practice discussing and disclosing a medical error that involves several professions, following a communication map. As they practice, students gain an understanding of the roles, skills, and perspectives of the other professions represented in the group. RESULTS: Over the last 5 years, student evaluations have been very positive. In 2016, our students strongly agreed that "The small group skills practice was a useful and interesting learning opportunity," "Learning with other professional students was valuable," and "Thinking about error disclosure from a team perspective was helpful." Student comments consistently indicated that they learned both about disclosing medical errors as well as other professionals' roles and perspectives. DISCUSSION: This activity has met both of our major goals. The first was to bring health professions students together to learn with, from, and about each other. The second was to practice a critical and challenging communication skill. This activity has been successfully implemented at other institutions, and can be adapted to fit other groups of students.

Inpatient management of diabetes.

Hyperglycemia is common in hospitalized patients with diabetes and contributes to poor outcomes in this population. Use of intravenous insulin protocols for patients who are unable to eat, continuation of usual insulin regimens for those who are eating, pre-meal insulin supplements for hyperglycemia, and avoidance of sliding-scale insulin can help the clinician improve glycemic control. Careful attention to management of diabetes in the hospitalized patient decreases the risk of ketoacidosis, fluid and electrolyte abnormalities, and infection; in critically ill postoperative patients, tight glucose control with insulin administration decreases the risk of death.

Differential effect of 14 free fatty acids in the expression of inflammation markers on human arterial coronary cells.

Cardiovascular disease is the leading cause of death in the United States, and circulating free fatty acids (FFAs) are known risk factors associated with cardiovascular inflammation. The influence of 14 dietary FFAs (including saturated, mono- and polyunsaturated, and trans) on the expression of inflammatory markers in human coronary arterial smooth muscle (HCASM) and endothelial (HCEC) cells using a cell culture model was investigated. HCASM and HCEC cell cultures were incubated with 200 µM of each FFA for 8 or 24 h, respectively, at 37 °C in a 5% CO2 humidified incubator. Inflammatory markers were assessed by ELISA or Western blot in the supernatant or cell lysates respectively. Results showed significant differences in the expression of inflammatory markers among the fatty acid treatments and the control, with myristic and palmitic acids being identified as the most and linoleic acid as the least pro-inflammatory. This suggests that FFAs may induce low-grade inflammation in human coronary arterial cells and provides more information on mode of action.

Safety of using a computerized rounding and sign-out system to reduce resident duty hours.

PURPOSE: To determine whether changing sign-out practices and decreasing the time spent in rounding and recopying patient data affect patient safety. Responding to limited resident duty hours, the University of Washington launched a computerized rounding and sign-out system ("UW Cores"). The system shortened duty hours by facilitating sign-out, decreasing rounding time, and sharply reducing the time spent in prerounds data recopying. METHOD: This 14-week, randomized, crossover study involved 14 inpatient resident teams (6 general surgery, 8 internal medicine) at two hospitals. The authors measured resident-reported deviations in expected care that occurred during cross-coverage, medical errors, and institutionally reported adverse drug events (ADEs). RESULTS: The mean number of resident-reported deviations from expected care per 1,000 patient-days did not differ significantly between the control and UW Cores groups: 14.29 and 13.81, respectively (P = .85). The mean number of reported incidents involving errors was 6.33 per 1,000 patient-days for the control group and 5.61 per 1,000 patient-days for the UW Cores group (P = .68). The odds ratio of a reported overnight medical error under the UW Cores system was 1.01 (95% CI: 0.64, 1.60; P = .96). The odds ratio of an ADE while a resident is on an intervention team was 1.10 (95% CI: 0.69, 1.74; P = .70). CONCLUSIONS: Managing information for sign-out and rounding with the UW Cores system, to reduce time spent in recopying patient data and in rounding on patients, improved continuity and enhanced resident efficiency without weakening systemic defenses against error or jeopardizing patient safety.