CARD14 SIGNALOSOME FORMATION IS ASSOCIATED WITH ITS ENDOSOMAL RELOCATION AND mTORC1-INDUCED KERATINOCYTE PROLIFERATION.

Rare mutations in CARD14 promote psoriasis by inducing CARD14-BCL10-MALT1 complexes that activate NF-kB and MAP kinases. Here, the downstream signalling mechanism of the highly penetrant CARD14E138Aalteration is described. In addition to BCL10 and MALT1, CARD14E138A associated with several proteins important in innate immune signalling. Interactions with M1-specific ubiquitin E3 ligase HOIP, and K63-specific ubiquitin E3 ligase TRAF6 promoted BCL10 ubiquitination and were essential for NF-kB and MAP kinase activation. In contrast, the ubiquitin binding proteins A20 and ABIN1, both genetically associated with psoriasis development, negatively regulated signalling by inducing CARD14E138A turnover. CARD14E138A localized to early endosomes and was associated with the AP2 adaptor complex. AP2 function was required for CARD14E138A activation of mTOR complex 1, which stimulated keratinocyte metabolism, but not for NF-kB nor MAP kinase activation. Furthermore, rapamycin ameliorated CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice, suggesting that blocking mTORC1 may be therapeutically beneficial in CARD14-dependent psoriasis.

Three Epochs of Artificial Intelligence in Health Care.

Importance: Interest in artificial intelligence (AI) has reached an all-time high, and health care leaders across the ecosystem are faced with questions about where, when, and how to deploy AI and how to understand its risks, problems, and possibilities. Observations: While AI as a concept has existed since the 1950s, all AI is not the same. Capabilities and risks of various kinds of AI differ markedly, and on examination 3 epochs of AI emerge. AI 1.0 includes symbolic AI, which attempts to encode human knowledge into computational rules, as well as probabilistic models. The era of AI 2.0 began with deep learning, in which models learn from examples labeled with ground truth. This era brought about many advances both in people's daily lives and in health care. Deep learning models are task-specific, meaning they do one thing at a time, and they primarily focus on classification and prediction. AI 3.0 is the era of foundation models and generative AI. Models in AI 3.0 have fundamentally new (and potentially transformative) capabilities, as well as new kinds of risks, such as hallucinations. These models can do many different kinds of tasks without being retrained on a new dataset. For example, a simple text instruction will change the model's behavior. Prompts such as "Write this note for a specialist consultant" and "Write this note for the patient's mother" will produce markedly different content. Conclusions and Relevance: Foundation models and generative AI represent a major revolution in AI's capabilities, ffering tremendous potential to improve care. Health care leaders are making decisions about AI today. While any heuristic omits details and loses nuance, the framework of AI 1.0, 2.0, and 3.0 may be helpful to decision-makers because each epoch has fundamentally different capabilities and risks.

Generative artificial intelligence, patient safety and healthcare quality: a review.

The capabilities of artificial intelligence (AI) have accelerated over the past year, and they are beginning to impact healthcare in a significant way. Could this new technology help address issues that have been difficult and recalcitrant problems for quality and safety for decades? While we are early in the journey, it is clear that we are in the midst of a fundamental shift in AI capabilities. It is also clear these capabilities have direct applicability to healthcare and to improving quality and patient safety, even as they introduce new complexities and risks. Previously, AI focused on one task at a time: for example, telling whether a picture was of a cat or a dog, or whether a retinal photograph showed diabetic retinopathy or not. Foundation models (and their close relatives, generative AI and large language models) represent an important change: they are able to handle many different kinds of problems without additional datasets or training. This review serves as a primer on foundation models' underpinnings, upsides, risks and unknowns-and how these new capabilities may help improve healthcare quality and patient safety.

Slow-wave sleep dysfunction in mild parkinsonism is associated with excessive beta and reduced delta oscillations in motor cortex.

Increasing evidence suggests slow-wave sleep (SWS) dysfunction in Parkinson's disease (PD) is associated with faster disease progression, cognitive impairment, and excessive daytime sleepiness. Beta oscillations (8-35 Hz) in the basal ganglia thalamocortical (BGTC) network are thought to play a role in the development of cardinal motor signs of PD. The role cortical beta oscillations play in SWS dysfunction in the early stage of parkinsonism is not understood, however. To address this question, we used a within-subject design in a nonhuman primate (NHP) model of PD to record local field potentials from the primary motor cortex (MC) during sleep across normal and mild parkinsonian states. The MC is a critical node in the BGTC network, exhibits pathological oscillations with depletion in dopamine tone, and displays high amplitude slow oscillations during SWS. The MC is therefore an appropriate recording site to understand the neurophysiology of SWS dysfunction in parkinsonism. We observed a reduction in SWS quantity (p = 0.027) in the parkinsonian state compared to normal. The cortical delta (0.5-3 Hz) power was reduced (p = 0.038) whereas beta (8-35 Hz) power was elevated (p = 0.001) during SWS in the parkinsonian state compared to normal. Furthermore, SWS quantity positively correlated with delta power (r = 0.43, p = 0.037) and negatively correlated with beta power (r = -0.65, p < 0.001). Our findings support excessive beta oscillations as a mechanism for SWS dysfunction in mild parkinsonism and could inform the development of neuromodulation therapies for enhancing SWS in people with PD.

Non-STEM majors COVID-19 vaccine impressions improve, and misconceptions resolve, after podcast assignment.

Misinformation regarding vaccine science decreased the receptiveness to COVID-19 vaccines, exacerbating the negative effects of the COVID-19 pandemic on society. To mitigate the negative societal impact of the COVID-19 pandemic, impactful and creative science communication was needed, yet little research has explored how to encourage COVID-19 vaccine acceptance and address misconceptions held by non-Science, Technology, Engineering and Mathematics majors (referred to as non-majors). We have previously demonstrated that including expert guest lectures in the vaccine module in the non-major introductory biology course helps combat students' vaccine hesitancy. In the present study, we further address how learning about vaccines impacts student knowledge and impressions of the COVID-19 vaccines through a podcast assignment. As a part of this assignment, non-majors created podcasts to address COVID-19 vaccine misconceptions of their choice. We coded pre and post, open-ended essay reflections (n = 40) to assess non-majors' knowledge and impressions of the COVID-19 vaccines. Non-majors' impressions of the vaccines improved following the podcast assignment with more than three times as many students reporting a positive view of the assignment than negative views. Notably, eight of the nine interviewed students still ended the course with misconceptions about the COVID-19 vaccines, such as the vaccines being unnecessary or causing fertility issues. In a post semi-structured interview following this assignment, students (n = 7) discussed the impact of looking into the specific misconceptions related to COVID-19 vaccines themselves, including improved science communication skills and understanding of different perspectives. Thus, podcasts can provide opportunities for students to improve engagement in valuable societal topics like vaccine literacy in the non-majors classroom.

Validation of the RBD Symptom Severity Scale in the North American Prodromal Synucleinopathy Consortium.

BACKGROUND AND OBJECTIVES: REM sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment. The International RBD Study Group developed the RBD Symptom Severity Scale (RBDSSS) to assess symptom severity for clinical or research use. We assessed the psychometric and clinimetric properties of the RBDSSS in participants enrolled in the North American Prodromal Synucleinopathy (NAPS) Consortium for RBD. METHODS: NAPS participants, who have polysomnogram-confirmed RBD, and their bedpartners completed the RBDSSS (participant and bedpartner versions). The RBDSSS contains 8 questions to assess the frequency and severity/impact of (1) dream content, (2) vocalizations, (3) movements, and (4) injuries associated with RBD. Total scores for participant (maximum score = 54) and bedpartner (maximum score = 38) questionnaires were derived by multiplying frequency and severity scores for each question. The Clinical Global Impression Scale of Severity (CGI-S) and RBD symptom frequency were assessed by a physician during a semistructured clinical interview with participants and, if available, bedpartners. Descriptive analyses, correlations between overall scores, and subitems were assessed, and item response analysis was performed to determine the scale's validity. RESULTS: Among 261 study participants, the median (interquartile range) score for the RBDSSS-PT (participant) was 10 (4-18) and that for the RBDSSS-BP (bedpartner) was 8 (4-15). The median CGI-S was 3 (3-4), indicating moderate severity. RBDSSS-BP scores were significantly lower in women with RBD (6 vs 9, p = 0.02), while there were no sex differences in RBDSSS-PT scores (8 vs 10.5, p = 0.615). Positive correlations were found between RBDSSS-PT vs RBDSSS-BP (Spearman rs = 0.561), RBDSSS-PT vs CGI-S (rs = 0.556), and RBDSSS-BP vs CGI-S (rs = 0.491, all p < 0.0001). Item response analysis showed a high discriminatory value (range 1.40-2.12) for the RBDSSS-PT and RBDSSS-BP (1.29-3.47). DISCUSSION: We describe the RBDSSS with adequate psychometric and clinimetric properties to quantify RBD symptom severity and good concordance between participant and bedpartner questionnaires and between RBDSSS scores and clinician-assessed global severity.

Comorbid neurotrauma increases neurodegenerative-relevant cognitive, motor, and autonomic dysfunction in patients with rapid eye movement sleep behavior disorder: a substudy of the North American Prodromal Synucleinopathy Consortium.

STUDY OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g. Parkinson's disease (PD), Lewy body dementia, and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD)-henceforth "neurotrauma" (NT)-increase the odds of RBD by ~2.5-fold and are associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD. METHODS: Participants ≥18 years with overnight polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal Synucleinopathy Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory, and autonomic function, were completed. This cross-sectional analysis compared cases (n = 24; RBD + NT) to controls (n = 96; RBD), matched for age (~60 years), sex (15% female), and years of education (~15 years). RESULTS: RBD + NT reported earlier RBD symptom onset (37.5 ±â€…11.9 vs. 52.2 ±â€…15.1 years of age) and a more severe RBD phenotype. Similarly, RBD + NT reported more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to RBD. No differences in olfaction or color vision were observed. CONCLUSIONS: This cross-sectional, matched case:control study shows individuals with RBD + NT have significantly worse neurological measures related to common features of an overt synucleinopathy. Confirmatory longitudinal studies are ongoing; however, these results suggest RBD + NT may be associated with more advanced neurological symptoms related to an evolving neurodegenerative process.