Efficacy of novel SPAK inhibitor ZT-1a derivatives (1c, 1d, 1g & 1h) on improving post-stroke neurological outcome and brain lesion in mice.

SPAK inhibitor ZT-1a was previously shown to be neuroprotective in murine ischemic stroke models. In this study, we further examined the efficacy of four ZT-1a derivatives (ZT-1c, -1d, -1g and -1h) on reducing stroke-induced sensorimotor function impairment and brain lesions. Vehicle control (Veh) or ZT-1 derivatives were administered via osmotic pump to adult C57BL/6J mice during 3-21 h post-stroke. Neurological behavior of these mice was assessed at days 1, 3, 5, and 7 post-stroke and MRI T2WI and DTI analysis was subsequently conducted in ex vivo brains. Veh-treated stroke mice displayed sensorimotor function deficits compared to Sham mice. In contrast, mice receiving ZT-1a derivatives displayed significantly lower neurological deficits at days 3-7 post-stroke (p < 0.05), with ZT-1a, ZT-1c and ZT-1d showing greater impact than ZT-1h and ZT-1g. ZT-1a treatment was the most effective in reducing brain lesion volume on T2WI and in preserving NeuN + neurons (p < 0.01), followed by ZT-1d > -1c > -1g > -1h. The Veh-treated stroke mice displayed white matter tissue injury, reflected by reduced fractional anisotropy (FA) or axial diffusivity (AD) values in external capsule, internal capsule and hippocampus. In contrast, only ZT-1a-as well as ZT-1c-treated stroke mice exhibited significantly higher FA and AD values. These findings demonstrate that post-stroke administration of SPAK inhibitor ZT-1a and its derivatives (ZT-1c and ZT-1d) is effective in protecting gray and white matter tissues in ischemic brains, showing a potential for ischemic stroke therapy development.

The Role of Metabolic Plasticity of Tumor-Associated Macrophages in Shaping the Tumor Microenvironment Immunity.

Cancer cells possess a high metabolic demand for their rapid proliferation, survival, and progression and thus create an acidic and hypoxic tumor microenvironment (TME) deprived of nutrients. Moreover, acidity within the TME is the central regulator of tumor immunity that influences the metabolism of the immune cells and orchestrates the local and systemic immunity, thus, the TME has a major impact on tumor progression and resistance to anti-cancer therapy. Specifically, myeloid cells, which include myeloid-derived suppressor cells (MDSC), dendritic cells, and tumor-associated macrophages (TAMs), often reprogram their energy metabolism, resulting in stimulating the angiogenesis and immunosuppression of tumors. This review summarizes the recent findings of glucose, amino acids, and fatty acid metabolism changes of the tumor-associated macrophages (TAMs), and how the altered metabolism shapes the TME and anti-tumor immunity. Multiple proton pumps/transporters are involved in maintaining the alkaline intracellular pH which is necessary for the glycolytic metabolism of the myeloid cells and acidic TME. We highlighted the roles of these proteins in modulating the cellular metabolism of TAMs and their potential as therapeutic targets for improving immune checkpoint therapy.

The sim must go on: adapting resident education to the COVID-19 pandemic using telesimulation.

The COVID-19 pandemic and social distancing rules necessitated the suspension of all in-person learning activities at our institution. Consequently, distance learning became essential. We adapted a high-fidelity immersive case-based simulation scenario for telesimulation by using the virtual meeting platform Zoom® to meet our curricular needs. The use of telesimulation to teach a complex case-based scenario is novel. Two cohorts of anesthesiology residents participated 2 weeks apart. All learners were located at home. Four faculty members conducted the telesimulation from different locations within our simulation center in the roles of director, simulation operator, confederate anesthesiologist, and confederate surgeon. The anesthesiologist performed tasks as directed by learners. The scenario was divided into four scenes to permit reflection on interventions/actions by the participants based on the clinical events as the scenario progressed, to facilitate intermittent debriefing and learner engagement. All residents were given a medical knowledge pretest before the telesimulation and a posttest and learner satisfaction survey at the conclusion. The scenario was authentic and immersive, represented an actual case, and provided the opportunity to practice lessons that could be applied in the clinical setting. Participants rated telesimulation a reasonable substitution for in-person learning and expressed gratitude for continuation of their simulation-based education in this format during the pandemic. Participants in the second cohort reported feeling more engaged (p = 0.008) and stimulated to think critically (p = 0.003). Audio quality was the most frequently noted limitation. Fifty-three residents completed both pre- and posttests. The two cohorts did not differ in knowledge pretest scores (62% vs 60%, p = 0.80) or posttest scores (78% vs. 77%, p = 0.87). Overall, knowledge scores improved with the telesimulation intervention (pretest mean = 61% [SD = 14%]; posttest mean = 78% [SD = 12%]; t (41) = - 7.89, p < 0.001). Thus, using a Zoom format, we demonstrated the feasibility of adapting a complex case for telesimulation and effective knowledge gain. Furthermore, we improved our process in real time based on participant feedback. Participants were satisfied with their learning experience, suggesting that this format may be used in other distance learning situations.

An Advanced Boot Camp for Pediatric Anesthesiology Fellows.

BACKGROUND: Managing pediatric crises necessitates the acquisition of unique skills and confidence in its execution. Our aim was to develop and assess a curriculum based on the constructivist learning environment to enhance learning, orientation, and preparation of graduating pediatric anesthesiology fellows. METHODS: Fifty pediatric anesthesiology fellows from 9 academic institutions in the United States were recruited for an advanced boot camp over a 2-year period. Training stations were developed using high-fidelity simulation, standardized patients, self-reflection modules, and facilitated discussions. The curriculum was evaluated using an anonymous survey that assessed knowledge, self-confidence, appropriateness of case-scenario complexity, and usefulness for transitioning into an independent practitioner on a Likert scale (1 = strongly disagree to 5 = strongly agree). Data points were expressed as the median and interquartile range (IQR). RESULTS: Ninety-eight percent of the fellows completed a survey. Fellow perceptions of the advanced boot camp was positive. The median scores (IQR) for knowledge, self-confidence, appropriateness of case complexity, and usefulness for transition in 2017 were 5 (3,5), 4.5 (3,5), 5 (3,5), and 5 (3,5), respectively, and 5 (3,5), 4.5 (3,5), 5 (4,5), and 5 (3,5), respectively, in 2018. The IQR in the assessment for an appropriate level of complexity for their level of training, narrowed in 2018 (4,5), when compared with 2017 (3,5). CONCLUSIONS: Fellow responses support the idea that the advanced boot camp provided tools and strategies for their transition. A narrowed IQR regarding the appropriate level of complexity of scenarios in 2018, when compared with 2017, might suggest an improvement in the curriculum.