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Question: Severe asthma and COPD exacerbations requiring hospitalization are linked to increased disease morbidity and healthcare costs. We sought to identify Electronic Health Record (EHR) features of severe asthma and COPD exacerbations and evaluate the performance of four machine learning (ML) and one deep learning (DL) model in predicting readmissions using EHR data. Study design and methods: Observational study between September 30, 2012, and December 31, 2017, of patients hospitalized with asthma and COPD exacerbations. Results: This study included 5,794 patients, 1,893 with asthma and 3,901 with COPD. Patients with asthma were predominantly female (n = 1288 [68%]), 35% were Black (n = 669), and 25% (n = 479) were Hispanic. Black (44 vs. 33%, p = 0.01) and Hispanic patients (30 vs. 24%, p = 0.02) were more likely to be readmitted for asthma. Similarly, patients with COPD readmissions included a large percentage of Blacks (18 vs. 10%, p < 0.01) and Hispanics (8 vs. 5%, p < 0.01). To identify patients at high risk of readmission index hospitalization data of a subset of 2,682 patients, 777 with asthma and 1,905 with COPD, was analyzed with four ML models, and one DL model. We found that multilayer perceptron, the DL method, had the best sensitivity and specificity compared to the four ML methods implemented in the same dataset. Interpretation: Multilayer perceptron, a deep learning method, had the best performance in predicting asthma and COPD readmissions, demonstrating that EHR and deep learning integration can improve high-risk patient detection. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells play a vital role in xenotransplantation rejection. One approach to induce NK cell immune tolerance is to prevent the NK cell-mediated direct killing of porcine cells by targeting the interaction of the activating receptor NKG2D and its ligands. However, the identity of porcine ligands for the human NKG2D receptor has remained elusive. Previous studies on porcine UL-16 binding protein 1 (pULBP-1) as a ligand for human NKG2D have yielded contradictory results. The goal of the present study was to clarify the role of pULBP-1 in the immune response and its interaction with human NKG2D receptor. To accomplish this, the CRISPR/Cas9 gene editing tool was employed to disrupt the porcine ULBP-1 gene in a 5-gene knockout porcine endothelial cell line (GGTA1, CMAH, β4galNT2, SLA-I α chain, and β-2 microglobulin, 5GKO). A colony with two allele mutations in pULBP-1 was established as a 6-gene knockout pig cell line (6GKO). We found that pULBP-1-deficient pig cells exhibited a reduced binding capacity to human NKG2D-Fc, a recombinant chimera protein. However, the removal of ULBP-1 from porcine endothelial cells did not significantly impact human NK cell degranulation or cytotoxicity upon stimulation with the pig cells. These findings conclusively demonstrate that pULBP-1 is not a crucial ligand for initiating xenogeneic human NK cell activation. [ABSTRACT FROM AUTHOR]

Mucinous cystic neoplasms (MCNs) are rare tumors of the liver, occasionally seen in the biliary tree. Epidemiologic data are limited by their indolence and recent changes to diagnostic criteria. They are considered premalignant lesions capable of invasive behavior. While their etiology remains unknown, their female predominance, age of onset, and hormonally responsive ovarian-type stroma suggest ectopic organogenesis during embryologic development. MCNs can typically be recognized on imaging; yet, invasiveness is often indeterminate, and percutaneous tissue biopsy has shown limited value. Therefore, complete excision is recommended for all lesions as focal malignant transformation and metastatic disease has been reported. [ABSTRACT FROM AUTHOR]

Physician turnover places a heavy burden on the healthcare industry, patients, physicians, and their families. Having a mechanism in place to identify physicians at risk for departure could help target appropriate interventions that prevent departure. We have collected physician characteristics, electronic health record (EHR) use patterns, and clinical productivity data from a large ambulatory based practice of non-teaching physicians to build a predictive model. We use several techniques to identify possible intervenable variables. Specifically, we used gradient boosted trees to predict the probability of a physician departing within an interval of 6 months. Several variables significantly contributed to predicting physician departure including tenure (time since hiring date), panel complexity, physician demand, physician age, inbox, and documentation time. These variables were identified by training, validating, and testing the model followed by computing SHAP (SHapley Additive exPlanation) values to investigate which variables influence the model's prediction the most. We found these top variables to have large interactions with other variables indicating their importance. Since these variables may be predictive of physician departure, they could prove useful to identify at risk physicians such who would benefit from targeted interventions. [ABSTRACT FROM AUTHOR]

Objectives To determine whether there may be a common mechanism resulting in global sensory impairment of the five classical senses (vision, smell, hearing, touch, and taste) in older adults. Design Representative, population-based study. Setting National Social Life, Health, and Aging Project. Participants Community-dwelling U.S. adults aged 57 to 85. Measurements The frequency with which impairment co-occurred across the five senses was estimated as an integrated measure of sensory aging. It was hypothesized that multisensory deficits would be common and reflect global sensory impairment that would largely explain the effects of age, sex, and race on sensory dysfunction. Results Two-thirds of subjects had two or more sensory deficits, 27% had just one, and 6% had none. Seventy-four percent had impairment in taste, 70% in touch, 22% in smell, 20% in corrected vision, and 18% in corrected hearing. Older adults, men, African Americans, and Hispanics had greater multisensory impairment (all P < .01). Global sensory impairment largely accounted for the effects of age, sex, and race on the likelihood of impairment in each of the five senses. Conclusion Multisensory impairment is prevalent in older U.S. adults. These data support the concept of a common process that underlies sensory aging across the five senses. Clinicians assessing individuals with a sensory deficit should consider further evaluation for additional co-occurring sensory deficits. [ABSTRACT FROM AUTHOR]

Context: Current information-rich electronic health record (EHR) interfaces require large, high-resolution screens running on desktop computers. This interface compromises the provider's already limited time at the bedside by physically separating the patient from the doctor. The case study presented here describes a patient-centered clinical decision support (CDS) design process that aims to bring the physician back to the bedside by integrating a patient decision aid with CDS for shared use by the patient and provider on a touchscreen tablet computer for deciding whether or not to obtain a CT scan for minor head injury in the emergency department, a clinical scenario that could benefit from CDS but has failed previous implementation attempts. Case Description: This case study follows the user-centered design (UCD) approach to build a bedside aid that is useful and usable, and that promotes shared decision-making between patients and their providers using a tablet computer at the bedside. The patient-centered decision support design process focuses on the prototype build using agile software development, but also describes the following: (1) the requirement gathering phase including triangulated qualitative research (focus groups and cognitive task analysis) to understand current challenges, (2) features for patient education, the physician, and shared decision-making, (3) system architecture and technical requirements, and (4) future plans for formative usability testing and field testing. Lessons Learned: We share specific lessons learned and general recommendations from critical insights gained in the patient-centered decision support design process about early stakeholder engagement, EHR integration, external expert feedback, challenges to two users on a single device, project management, and accessibility. Conclusions: Successful implementation of this tool will require seamless integration into the provider's workflow. This protocol can create an effective interface for shared decision-making and safe resource reduction at the bedside in the austere and dynamic clinical environment of the ED and is generalizable for these purposes in other clinical environments as well. [ABSTRACT FROM AUTHOR]

The Hippo pathway plays a central role in tissue development and homeostasis. However, the function of Hippo in pancreatic endocrine development remains obscure. Here, we generated novel conditional genetically engineered mouse models to examine the roles of Hippo pathway-mediated YAP1/TAZ inhibition in the development stages of endocrine specification and differentiation. While YAP1 protein was localized to the nuclei in bipotent progenitor cells, Neurogenin 3 expressing endocrine progenitors completely lost YAP1 expression. Using genetically engineered mouse models, we found that inactivation of YAP1 requires both an intact Hippo pathway and Neurogenin 3 protein. Gene deletion of Lats1 and 2 kinases (Lats1&2) in endocrine progenitor cells of developing mouse pancreas using Neurog3Cre blocked endocrine progenitor cell differentiation and specification, resulting in reduced islets size and a disorganized pancreas at birth. Loss of Lats1&2 in Neurogenin 3 expressing cells activated YAP1/TAZ transcriptional activity and recruited macrophages to the developing pancreas. These defects were rescued by deletion of Yap1/Wwtr1 genes, suggesting that tight regulation of YAP1/TAZ by Hippo signaling is crucial for pancreatic endocrine specification. In contrast, deletion of Lats1&2 using β-cell-specific Ins1CreER resulted in a phenotypically normal pancreas, indicating that Lats1&2 are indispensable for differentiation of endocrine progenitors but not for that of β-cells. Our results demonstrate that loss of YAP1/TAZ expression in the pancreatic endocrine compartment is not a passive consequence of endocrine specification. Rather, Hippo pathway-mediated inhibition of YAP1/TAZ in endocrine progenitors is a prerequisite for endocrine specification and differentiation. [ABSTRACT FROM AUTHOR]

Xenotransplantation (cross-species transplantation) using genetically-engineered pig organs offers a potential solution to address persistent organ shortage. Current evaluation of porcine genetic modifications is to monitor the nonhuman primate immune response and survival after pig organ xenotransplantation. This measure is an essential step before clinical xenotransplantation trials, but it is time-consuming, costly, and inefficient with many variables. We developed an efficient approach to quickly examine human-to-pig xeno-immune responses in vitro. A porcine endothelial cell was characterized and immortalized for genetic modification. Five genes including GGTA1, CMAH, β4galNT2, SLA-I α chain, and β2-microglobulin that are responsible for the production of major xenoantigens (αGal, Neu5Gc, Sda, and SLA-I) were sequentially disrupted in immortalized porcine endothelial cells using CRISPR/Cas9 technology. The elimination of αGal, Neu5Gc, Sda, and SLA-I dramatically reduced the antigenicity of the porcine cells, though the cells still retained their ability to provoke human natural killer cell activation. In summary, evaluation of human immune responses to genetically modified porcine cells in vitro provides an efficient method to identify ideal combinations of genetic modifications for improving pig-to-human compatibility, which should accelerate the application of xenotransplantation to humans. [ABSTRACT FROM AUTHOR]

Objective: We aimed to discover computationally-derived phenotypes of opioid-related patient presentations to the ED via clinical notes and structured electronic health record (EHR) data. Methods: This was a retrospective study of ED visits from 2013–2020 across ten sites within a regional healthcare network. We derived phenotypes from visits for patients ≥18 years of age with at least one prior or current documentation of an opioid-related diagnosis. Natural language processing was used to extract clinical entities from notes, which were combined with structured data within the EHR to create a set of features. We performed latent dirichlet allocation to identify topics within these features. Groups of patient presentations with similar attributes were identified by cluster analysis. Results: In total 82,577 ED visits met inclusion criteria. The 30 topics were discovered ranging from those related to substance use disorder, chronic conditions, mental health, and medical management. Clustering on these topics identified nine unique cohorts with one-year survivals ranging from 84.2–96.8%, rates of one-year ED returns from 9–34%, rates of one-year opioid event 10–17%, rates of medications for opioid use disorder from 17–43%, and a median Carlson comorbidity index of 2–8. Two cohorts of phenotypes were identified related to chronic substance use disorder, or acute overdose. Conclusions: Our results indicate distinct phenotypic clusters with varying patient-oriented outcomes which provide future targets better allocation of resources and therapeutics. This highlights the heterogeneity of the overall population, and the need to develop targeted interventions for each population. [ABSTRACT FROM AUTHOR]

Despite the rising prevalence of nonalcoholic fatty liver disease (NAFLD), the underlying disease pathophysiology remains unclear. There is a great need for an efficient and reliable "human" in vitro model to study NAFLD and the progression to nonalcoholic steatohepatitis (NASH), which will soon become the leading indication for liver transplantation. Here, we review the recent developments in the use of three-dimensional (3D) liver organoids as a model to study NAFLD and NASH pathophysiology and possible treatments. Various techniques that are currently used to make liver organoids are discussed, such as the use of induced pluripotent stem cells versus primary cell lines and human versus murine cells. Moreover, methods for inducing lipid droplet accumulation and fibrosis to model NAFLD are explored. Finally, the limitations specific to the 3D organoid model for NAFLD/NASH are reviewed, highlighting the need for further development of multilineage models to include hepatic nonparenchymal cells and immune cells. The ultimate goal is to be able to accurately recapitulate the complex liver microenvironment in which NAFLD develops and progresses to NASH. [ABSTRACT FROM AUTHOR]

Objectives To evaluate global sensory impairment ( GSI, an integrated measure of sensory dysfunction) as a predictor of physical function, cognition, overall health, and mortality. Design Prospective study. Setting The National Social Life, Health, and Aging Project. Participants A national probability sample of 3,005 home-dwelling older U.S. adults assessed at baseline (2005-06) and 5-year follow-up (2010-11). Measurements Gait speed, activity, disability, cognition, overall health, 5-year mortality. Results At baseline, older adults with worse GSI were slower (Timed Up and Go times: odds ratio ( OR) = 1.32, 95% confidence interval ( CI) = 1.17-1.50) and had more activity of daily living deficits (≥2: OR = 1.26, 95% CI = 1.10-1.46). Five years later, they were still slower (timed walk: OR = 1.22, 95% CI = 1.05-1.42), had more disabilities (≥2 instrumental activities of daily living; OR = 1.45, 95% CI = 1.23-1.70), were less active (daytime activity according to accelerometry: β = −2.7, 95% CI = −5.2 to −0.2), had worse cognitive function (Montreal Cognitive Assessment; β = −0.64, 95% CI = −0.84 to −0.44), more likely to have poorer overall health (OR = 1.16, 95% CI = 1.03-1.31) and lose weight (>10%: OR = 1.31, 95% CI = 1.04-1.64), and have died ( OR = 1.45, 95% CI = 1.19-1.76). All analyses were adjusted for relevant confounders at baseline, including age, sex, race and ethnicity, education, smoking, problem drinking, body mass index, comorbidities, and cognitive function. Conclusion GSI predicts impaired physical function, cognitive dysfunction, significant weight loss, and mortality 5 years later in older U.S. adults. Multisensory evaluation may identify vulnerable individuals, offering the opportunity for early intervention to mitigate adverse outcomes. [ABSTRACT FROM AUTHOR]

Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d+/- retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of lightinduced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration. [ABSTRACT FROM AUTHOR]

Summary: Parkinson’s disease (PD) is characterized by loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). An association has been reported between PD and exposure to mitochondrial toxins, including environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived stem cell model of PD allowing comparison of A53T α-synuclein (α-syn) mutant cells and isogenic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations in A53T α-syn A9 DA neurons (hNs). We report a pathway whereby basal and toxin-induced nitrosative/oxidative stress results in S-nitrosylation of transcription factor MEF2C in A53T hNs compared to corrected controls. This redox reaction inhibits the MEF2C-PGC1α transcriptional network, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small-molecule high-throughput screening, we identify the MEF2C-PGC1α pathway as a therapeutic target to combat PD. [ABSTRACT FROM AUTHOR]

Objective: Teleretinal screening with nonmydriatic cameras has been presented as a means of increasing the number of patients assessed for diabetic retinopathy in urban safety net clinics. It has been hypothesized that automated nonmydriatic cameras may improve screening rates by reducing the learning curve for camera use. In this article, we examine the impact of introducing automated nonmydriatic cameras to urban safety net clinics whose photographers had previously used manual cameras. Materials and Methods: We evaluated the impact of manual and automated digital nonmydriatic cameras on teleretinal screening using a quantitative analysis of readers' image quality ratings as well as a qualitative analysis, through in-depth interviews, of photographers' experiences. Results: With the manual camera, 68% of images were rated 'adequate' or better, including 24% rated 'good' and 20% rated 'excellent.' With the automated camera, 61% were rated 'adequate' or better, including 9% rated 'good' and 0% rated 'excellent.' Photographers expressed frustration with their inability to control image-taking settings with the automated camera, which led to unexpected delays. Conclusions: For safety net clinics in which medical assistants are already trained to take photographs for diabetic retinopathy screening with a manual camera, the introduction of automated cameras may lead to frustration and paradoxically contribute to increased patient wait times. When photographers have achieved a high degree of aptitude with manual cameras and value the control they have over camera features, the introduction of automated cameras should be approached with caution and may require extensive training to increase user acceptability. [ABSTRACT FROM AUTHOR]

Background & Aims: Liver fibrosis is a pathological healing process resulting from hepatic stellate cell (HSC) activation and the generation of myofibroblasts from activated HSCs. The precise underlying mechanisms of liver fibrogenesis are still largely vague due to lack of understanding the functional heterogeneity of activated HSCs during liver injury. Approach and Results: In this study, to define the mechanism of HSC activation, we performed the transcriptomic analysis at single-cell resolution (scRNA-seq) on HSCs in mice treated with carbon tetrachloride (CCl4). By employing LRAT-Cre:Rosa26mT/mG mice, we were able to isolate an activated GFP-positive HSC lineage derived cell population by fluorescence-activated cell sorter (FACS). A total of 8 HSC subpopulations were identified based on an unsupervised analysis. Each HSC cluster displayed a unique transcriptomic profile, despite all clusters expressing common mouse HSC marker genes. We demonstrated that one of the HSC subpopulations expressed high levels of mitosis regulatory genes, velocity, and monocle analysis indicated that these HSCs are at transitioning and proliferating phases at the beginning of HSCs activation and will eventually give rise to several other HSC subtypes. We also demonstrated cell clusters representing HSC-derived mature myofibroblast populations that express myofibroblasts hallmark genes with unique contractile properties. Most importantly, we found a novel HSC cluster that is likely to be critical in liver regeneration, immune reaction, and vascular remodeling, in which the unique profiles of genes such as Rgs5, Angptl6, and Meg3 are highly expressed. Lastly, we demonstrated that the heterogeneity of HSCs in the injured mouse livers is closely similar to that of cirrhotic human livers. Conclusions: Collectively, our scRNA-seq data provided insight into the landscape of activated HSC populations and the dynamic transitional pathway from HSC to myofibroblasts in response to liver injury. [ABSTRACT FROM AUTHOR]

The article focuses on origin of formation of SNO-Drp1, revealing a previously unknown network of transnitrosylation reactions in Alzheimer's disease (AD). It mentions cognitive decline in AD, this nitrosylation reaction represents an important potential contributor to disease pathogenesis. It also mentions SNO-Drp1 via a reaction termed transnitrosylation, additional members of this pathological cascade.