ß-cell-selective inhibition of DNA damage response signaling by nitric oxide is associated with an attenuation in glucose uptake.

Nitric oxide (NO) plays a dual role in regulating DNA damage response (DDR) signaling in pancreatic ß-cells. As a genotoxic agent, NO activates two types of DDR signaling; however, when produced at micromolar levels by the inducible isoform of NO synthase, NO inhibits DDR signaling and DDR-induced apoptosis in a ß-cell-selective manner. DDR signaling inhibition by NO correlates with mitochondrial oxidative metabolism inhibition and decreases in ATP and NAD+. Unlike most cell types, ß-cells do not compensate for impaired mitochondrial oxidation by increasing glycolytic flux, and this metabolic inflexibility leads to a decrease in ATP and NAD+. Here, we used multiple analytical approaches to determine changes in intermediary metabolites in ß-cells and non-ß-cells treated with NO or complex I inhibitor rotenone. In addition to ATP and NAD+, glycolytic and tricarboxylic acid cycle intermediates as well as NADPH are significantly decreased in ß-cells treated with NO or rotenone. Consistent with glucose-6-phosphate residing at the metabolic branchpoint for glycolysis and the pentose phosphate pathway (NADPH), we show that mitochondrial oxidation inhibitors limit glucose uptake in a ß-cell-selective manner. Our findings indicate that the ß-cell-selective inhibition of DDR signaling by NO is associated with a decrease in ATP to levels that fall significantly below the KM for ATP of glucokinase (glucose uptake) and suggest that this action places the ß-cell in a state of suspended animation where it is metabolically inert until NO is removed, and metabolic function can be restored.

Development of a rapid lateral flow assay for detection of anti-coccidioidal antibodies.

Coccidioides spp. are dimorphic fungi that are capable of infecting human and non-human mammals and can cause diverse manifestations of coccidioidomycosis or Valley fever (VF). In combination with clinical symptoms and radiographic findings, antibody-based diagnostic tests are often used to diagnose and monitor patients with VF. Chitinase 1 (CTS1) has previously been identified as the seroreactive antigen used in these diagnostic assays to detect anticoccidial IgG. Here, an indirect enzyme-linked immunosorbent assay to detect IgG to CTS1 demonstrated 165 of 178 (92.7%) patients with a positive result by immunodiffusion (ID) and/or complement fixation (CF) had antibodies to the single antigen CTS1. We then developed a rapid antibody lateral flow assay (LFA) to detect anti-CTS1 antibodies. Out of 143 samples tested, the LFA showed 92.9% positive percent agreement [95% confidence interval (CI), 84.3%-96.9%] and 97.7% negative percent agreement (95% CI, 87.9%-99.6%) with ID and CF assays. Serum or plasma from canines, macaques, and dolphins was also tested by the CTS1 LFA. Test line densities of the CTS1 LFA correlated in a linear manner with the reported CF and ID titers for human and non-human samples, respectively. This 10-min point-of-care test for the rapid detection of anti-coccidioidal antibodies could help to inform healthcare providers in real-time, potentially improving the efficiency of healthcare delivery.

SUPERFICIAL CERVICAL LYMPHADENITIS ASSOCIATED WITH STREPTOCOCCUS PHOCAE IN FIVE COMMON BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS): A CASE SERIES.

Between 2009 and 2018, five common bottlenose dolphins (Tursiops truncatus) at the US Navy Marine Mammal Program presented with superficial cervical lymphadenitis. Clinical findings included ultrasonographic evidence of cervical lymph node enlargement, severe leukocytosis, elevated erythrocyte sedimentation rates, and reduced serum iron. Three of the dolphins presented with clinicopathologic changes without presence of clinical signs, and the other two cases additionally presented with partial to complete anorexia, lethargy, and refusal to participate in training sessions. Ultrasound-guided fine needle aspiration or biopsy of the affected lymph nodes yielded Streptococcus phocae by PCR in all cases, and the organism was cultured in one of five cases. Animals were treated with a combination of enteral, parenteral, intralesional antimicrobial, or a combination of those therapies and supportive care. Time to resolution of clinical disease ranged between 62 and 188 days. To the authors' knowledge, this is the first report of Streptococcus phocae cervical lymphadenitis in cetaceans. Streptococcus phocae lymphadenitis should be a differential for cervical lymphadenopathy in this species, especially when associated with pronounced systemic inflammation and a history of potential exposure.

Detection and Characterization of New Coronavirus in Bottlenose Dolphin, United States, 2019.

We characterized novel coronaviruses detected in US bottlenose dolphins (BdCoVs) with diarrhea. These viruses are closely related to the other 2 known cetacean coronaviruses, Hong Kong BdCoV and beluga whale CoV. A deletion in the spike gene and insertions in the membrane gene and untranslated regions were found in US BdCoVs (unrelated to severe acute respiratory syndrome coronavirus 2).

Contextualizing Instructional Technology to the Demands of Nursing Education.

This article reviews current technologies in nursing education and the impact of technology on learning. The integration of technology into nursing curricula is thought to improve efficiency and enhance student experiences through active learning and interactive learning designs. The following focused questions are explored: (1) What are the current technologies used by university students and faculty in nursing programs? (2) How does that technology influence student learning? The primary themes were student-centered technology, with five subthemes, and faculty-centered technology. Consumers of healthcare (patients) demand quality care and expect highly skilled, compassionate, ethical practitioners; to this end, training and education of future nurses by skilled, qualified nurse educators who are comfortable with technological demands of all aspects of healthcare are fundamental. While it is essential that nurses and nurse educators continue to publish as a mechanism for open discussion and transparency in our teaching and learning approaches, we need higher levels of evidence to strengthen the argument that technology improves the learning environment and student outcomes and has a positive impact on clinical settings and patient care.

Toward Dynamically Adaptive Simulation: Multimodal Classification of User Expertise Using Wearable Devices.

Simulation-based training has been proven to be a highly effective pedagogical strategy. However, misalignment between the participant's level of expertise and the difficulty of the simulation has been shown to have significant negative impact on learning outcomes. To ensure that learning outcomes are achieved, we propose a novel framework for adaptive simulation with the goal of identifying the level of expertise of the learner, and dynamically modulating the simulation complexity to match the learner's capability. To facilitate the development of this framework, we investigate the classification of expertise using biological signals monitored through wearable sensors. Trauma simulations were developed in which electrocardiogram (ECG) and galvanic skin response (GSR) signals of both novice and expert trauma responders were collected. These signals were then utilized to classify the responders' expertise, successive to feature extraction and selection, using a number of machine learning methods. The results show the feasibility of utilizing these bio-signals for multimodal expertise classification to be used in adaptive simulation applications.

Integrating trauma-informed services in out-of-school time programs to mitigate the impact of community gun violence on youth mental health.

Community gun violence disproportionately impacts youth in low-income urban neighborhoods. Integrating trauma-informed mental health care in community-based out-of-school time (OST) programs is an innovative method of service delivery for these youth. This article provides justification for integrating evidence-based, trauma-informed services in OST programs within communities characterized by high rates of violent crime to minimize the impact of violence exposure on youth mental health. We describe the initial feasibility of a model program, the Violence Intervention and Prevention (VIP) Initiative, implemented in a small city in southeastern Pennsylvania. Within the first six months of the VIP Initiative, 95 community residents (90% under age 18; 51% Hispanic) received intervention services, primarily through single-session and short-term weekly group intervention in OST programs, and 80% of OST youth development staff participated in at least one trauma-informed professional development training. Recommendations to enhance and expand the delivery of trauma-informed services in the novel setting of OST programs are provided.

The variable domain from the mitochondrial fission mechanoenzyme Drp1 promotes liquid-liquid phase separation.

Dynamins are an essential superfamily of mechanoenzymes that remodel membranes and often contain a "variable domain" (VD) important for regulation. For the mitochondrial fission dynamin, Drp1, a regulatory role for the VD is demonstrated by mutations that can elongate, or fragment, mitochondria. How the VD encodes inhibitory and stimulatory activity is unclear. Here, isolated VD is shown to be intrinsically disordered (ID) yet undergoes a cooperative transition in the stabilizing osmolyte TMAO. However, the TMAO stabilized state is not folded and surprisingly appears as a condensed state. Other co-solutes including known molecular crowder Ficoll PM 70, also induce a condensed state. Fluorescence recovery after photobleaching experiments reveal this state to be liquid-like indicating the VD undergoes a liquid-liquid phase separation under crowding conditions. These crowding conditions also enhance binding to cardiolipin, a mitochondrial lipid, raising the possibility that phase separation may enable rapid tuning of Drp1 assembly necessary for fission.

The variable domain from dynamin-related protein 1 promotes liquid-liquid phase separation that enhances its interaction with cardiolipin-containing membranes.

Dynamins are an essential superfamily of mechanoenzymes that remodel membranes and often contain a "variable domain" important for regulation. For the mitochondrial fission dynamin, dynamin-related protein 1, a regulatory role for the variable domain (VD) is demonstrated by gain- and loss-of-function mutations, yet the basis for this is unclear. Here, the isolated VD is shown to be intrinsically disordered and undergo a cooperative transition in the stabilizing osmolyte trimethylamine N-oxide. However, the osmolyte-induced state is not folded and surprisingly appears as a condensed state. Other co-solutes including known molecular crowder Ficoll PM 70, also induce a condensed state. Fluorescence recovery after photobleaching experiments reveal this state to be liquid-like indicating the VD undergoes a liquid-liquid phase separation under crowding conditions. These crowding conditions also enhance binding to cardiolipin, a mitochondrial lipid, which appears to promote phase separation. Since dynamin-related protein 1 is found assembled into discrete punctate structures on the mitochondrial surface, the inference from the present work is that these structures might arise from a condensed state involving the VD that may enable rapid tuning of mechanoenzyme assembly necessary for fission.

The future of simulation-based medical education: Adaptive simulation utilizing a deep multitask neural network.

BACKGROUND: In resuscitation medicine, effectively managing cognitive load in high-stakes environments has important implications for education and expertise development. There exists the potential to tailor educational experiences to an individual's cognitive processes via real-time physiologic measurement of cognitive load in simulation environments. OBJECTIVE: The goal of this research was to test a novel simulation platform that utilized artificial intelligence to deliver a medical simulation that was adaptable to a participant's measured cognitive load. METHODS: The research was conducted in 2019. Two board-certified emergency physicians and two medical students participated in a 10-minute pilot trial of a novel simulation platform. The system utilized artificial intelligence algorithms to measure cognitive load in real time via electrocardiography and galvanic skin response. In turn, modulation of simulation difficulty, determined by a participant's cognitive load, was facilitated through symptom severity changes of an augmented reality (AR) patient. A postsimulation survey assessed the participants' experience. RESULTS: Participants completed a simulation that successfully measured cognitive load in real time through physiological signals. The simulation difficulty was adapted to the participant's cognitive load, which was reflected in changes in the AR patient's symptoms. Participants found the novel adaptive simulation platform to be valuable in supporting their learning. CONCLUSION: Our research team created a simulation platform that adapts to a participant's cognitive load in real-time. The ability to customize a medical simulation to a participant's cognitive state has potential implications for the development of expertise in resuscitation medicine.

Geriatric referral patterns for physical therapy: a descriptive analysis.

PURPOSE: The purposes of this study were to: (1) describe older adults being seen for physical therapy, (2) identify the most prevalent physician orders and physical therapy interventions, and (3) compare these results across US regions. METHODS: A written questionnaire was mailed to a random sample of 1600 therapists. Therapists completed information for up to 10 patients including classification of diagnosis according to the Guide to Physical Therapist Practice. ANALYSIS: Descriptive analyses were performed. RESULTS: 118 therapists provided information on 839 patients. More of the patients were women (65%) than men (35%); their average age was 76.4 years. Most patients were seen in the outpatient setting (56%) and over 70% were classified into one of the musculoskeletal diagnostic categories. "Evaluate and treat" was present in 66.2% of the physician orders. The 6 most frequently performed interventions were in the therapeutic exercise category. CONCLUSION: Many physical therapists, even those who may not consider themselves geriatric physical therapists, are seeing older adults in a variety of settings. Knowledge about the diverse needs of older adults, therefore, is important for clinicians and students to meet the rising demand for quality physical therapy for this population.