Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia.

The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse cortical neurons and neurons derived from control human induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS/FTD.

Characterizing and predicting ccRCC-causing missense mutations in Von Hippel-Lindau disease.

BACKGROUND: Mutations within the Von Hippel-Lindau (VHL) tumor suppressor gene are known to cause VHL disease, which is characterized by the formation of cysts and tumors in multiple organs of the body, particularly clear cell renal cell carcinoma (ccRCC). A major challenge in clinical practice is determining tumor risk from a given mutation in the VHL gene. Previous efforts have been hindered by limited available clinical data and technological constraints. METHODS: To overcome this, we initially manually curated the largest set of clinically validated VHL mutations to date, enabling a robust assessment of existing predictive tools on an independent test set. Additionally, we comprehensively characterized the effects of mutations within VHL using in silico biophysical tools describing changes in protein stability, dynamics and affinity to binding partners to provide insights into the structure-phenotype relationship. These descriptive properties were used as molecular features for the construction of a machine learning model, designed to predict the risk of ccRCC development as a result of a VHL missense mutation. RESULTS: Analysis of our model showed an accuracy of 0.81 in the identification of ccRCC-causing missense mutations, and a Matthew's Correlation Coefficient of 0.44 on a non-redundant blind test, a significant improvement in comparison to the previous available approaches. CONCLUSION: This work highlights the power of using protein 3D structure to fully explore the range of molecular and functional consequences of genomic variants. We believe this optimized model will better enable its clinical implementation and assist guiding patient risk stratification and management.

Educational, psychosocial, and clinical impact of SARS-CoV-2 (COVID-19) pandemic on medical students in the United States.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic altered education, exams, and residency applications for United States medical students. AIM: To determine the specific impact of the pandemic on US medical students and its correlation to their anxiety levels. METHODS: An 81-question survey was distributed via email, Facebook and social media groups using REDCapTM. To investigate risk factors associated with elevated anxiety level, we dichotomized the 1-10 anxiety score into low (≤ 5) and high (≥ 6). This cut point represents the 25th percentile. There were 90 (29%) shown as low anxiety and 219 (71%) as high anxiety. For descriptive analyses, we used contingency tables by anxiety categories for categorical measurements with chi square test, or mean ± STD for continuous measurements followed by t-test or Wilcoxson rank sum test depending on data normality. Least Absolute Shrinkage and Selection Operator was used to select important predictors for the final multivariate model. Hierarchical Poisson regression model was used to fit the final multivariate model by considering the nested data structure of students clustered within State. RESULTS: 397 medical students from 29 states were analyzed. Approximately half of respondents reported feeling depressed since the pandemic onset. 62% of participants rated 7 or higher out of 10 when asked about anxiety levels. Stressors correlated with higher anxiety scores included "concern about being unable to complete exams or rotations if contracting COVID-19" (RR 1.34; 95%CI: 1.05-1.72, P = 0.02) and the use of mental health services such as a "psychiatrist" (RR 1.18; 95%CI: 1.01-1.3, P = 0.04). However, those students living in cities that limited restaurant operations to exclusively takeout or delivery as the only measure of implementing social distancing (RR 0.64; 95%CI: 0.49-0.82, P < 0.01) and those who selected "does not apply" for financial assistance available if needed (RR 0.83; 95%CI: 0.66-0.98, P = 0.03) were less likely to have a high anxiety. CONCLUSION: COVID-19 significantly impacted medical students in numerous ways. Medical student education and clinical readiness were reduced, and anxiety levels increased. It is vital that medical students receive support as they become physicians. Further research should be conducted on training medical students in telemedicine to better prepare students in the future for pandemic planning and virtual healthcare.

Cough Sounds Recorded via Smart Devices as Useful Non-Invasive Digital Biomarkers of Aspiration Risk: A Case Report.

Spirometer measurements can reflect cough strength but might not be routinely available for patients with severe neurological or medical conditions. A digital device that can record and help track abnormal cough sound changes serially in a noninvasive but reliable manner would be beneficial for monitoring such individuals. This report includes two cases of respiratory distress whose cough changes were monitored via assessments performed using recordings made with a digital device. The cough sounds were recorded using an iPad (Apple, Cupertino, CA, USA) through an embedded microphone. Cough sounds were recorded at the bedside, with no additional special equipment. The two patients were able to complete the recordings with no complications. The maximum root mean square values obtained from the cough sounds were significantly reduced when both cases were diagnosed with aspiration pneumonia. In contrast, higher values became apparent when the patients demonstrated a less severe status. Based on an analysis of our two cases, the patients' cough sounds recorded with a commercial digital device show promise as potential digital biomarkers that may reflect aspiration risk related to attenuated cough force. Serial monitoring aided the decision making to resume oral feeding. Future studies should further explore the clinical utility of this technique.

Impacts of the Coronavirus Disease 2019 (COVID-19) pandemic on healthcare workers: A nationwide survey of United States radiologists.

BACKGROUND: Efforts to reduce nosocomial spread of COVID-19 have resulted in unprecedented disruptions in clinical workflows and numerous unexpected stressors for imaging departments across the country. Our purpose was to more precisely evaluate these impacts on radiologists through a nationwide survey. METHODS: A 43-item anonymous questionnaire was adapted from the AO Spine Foundation's survey and distributed to 1521 unique email addresses using REDCap™ (Research Electronic Data Capture). Additional invitations were sent out to American Society of Emergency Radiology (ASER) and Association of University Radiologists (AUR) members. Responses were collected over a period of 8 days. Descriptive analyses and multivariate modeling were performed using SAS v9.4 software. RESULTS: A total of 689 responses from radiologists across 44 different states met the criteria for inclusion in the analysis. As many as 61% of respondents rated their level of anxiety with regard to COVID-19 to be a 7 out of 10 or greater, and higher scores were positively correlated the standardized number of COVID-19 cases in a respondent's state (RR = 1.11, 95% CI: 1.02-1.21, p = 0.01). Citing the stressor of "personal health" was a strong predictor of higher anxiety scores (RR 1.23; 95% CI: 1.13-1.34, p < 0.01). By contrast, participants who reported needing no coping methods were more likely to self-report lower anxiety scores (RR 0.4; 95% CI: 0.3-0.53, p < 0.01). CONCLUSION: COVID-19 has had a significant impact on radiologists across the nation. As these unique stressors continue to evolve, further attention must be paid to the ways in which we may continue to support radiologists working in drastically altered practice environments and in remote settings.

Three case reports of laparoscopic management of granulosa cell tumor with intraoperative rupture and subsequent upstaging.

Granulosa cell tumors (GCT) of the ovary account for 2% to 5% of all ovarian tumors and typically demonstrate an indolent clinical course. For a young woman with stage IA disease who wishes to preserve fertility, conservative surgery with laparoscopic techniques can be a safe and effective method. Three patients with clinical presumptive stage IA GCT of the ovary were initially treated with conservative laparoscopic surgery with intraoperative rupture of the tumor. On repeat surgical exploration, all 3 patients were found to have peritoneal disease. Postoperative chemotherapy was required. Several important aspects of laparoscopic management of adnexal masses are highlighted by these 3 case reports. A thorough knowledge about GCT is important. Complete and clean removal of an unknown adnexal mass is imperative.