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ObjectiveClinical guidelines recommend annual eye examinations to detect diabetic retinopathy (DR) in patients with diabetes. However, timely DR detection remains a problem in medically underserved and under-resourced settings in the United States. Machine learning that identifies patients with latent/undiagnosed DR could help to address this problem.Materials and methodsUsing electronic health record data from 40 631 unique diabetic patients seen at Los Angeles County Department of Health Services healthcare facilities between January 1, 2015 and December 31, 2017, we compared ten machine learning environments, including five classifier models, for assessing the presence or absence of DR. We also used data from a distinct set of 9300 diabetic patients seen between January 1, 2018 and December 31, 2018 as an external validation set.ResultsFollowing feature subset selection, the classifier with the best AUC on the external validation set was a deep neural network using majority class undersampling, with an AUC of 0.8, the sensitivity of 72.17%, and specificity of 74.2%.DiscussionA deep neural network produced the best AUCs and sensitivity results on the test set and external validation set. Models are intended to be used to screen guideline noncompliant diabetic patients in an urban safety-net setting.ConclusionMachine learning on diabetic patients' routinely collected clinical data could help clinicians in safety-net settings to identify and target unscreened diabetic patients who potentially have undiagnosed DR.

Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function-transnitrosylation-that triggers a pathological biochemical cascade in mouse models and in humans with Alzheimer's disease (AD). The resulting series of transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the postreproductive period, so natural selection against such abnormal activity may be decreased.

Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c +/-(Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death. Accordingly, Mef2c-het mice exhibit decreased neurogenesis, enhanced neuronal apoptosis, and an increased ratio of excitatory to inhibitory (E/I) neurotransmission. Importantly, neurobehavioral deficits, E/I imbalance, and histological damage are all ameliorated by treatment with NitroSynapsin, a new dual-action compound related to the FDA-approved drug memantine, representing an uncompetitive/fast off-rate antagonist of NMDA-type glutamate receptors. These results suggest that MEF2C haploinsufficiency leads to abnormal brain development, E/I imbalance, and neurobehavioral dysfunction, which may be mitigated by pharmacological intervention.

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 light-induced 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.

Alzheimer's disease (AD) is characterized by synaptic and neuronal loss, which occurs at least partially through oxidative stress induced by oligomeric amyloid-β (Aβ)-peptide. Carnosic acid (CA), a chemical found in rosemary and sage, is a pro-electrophilic compound that is converted to its active form by oxidative stress. The active form stimulates the Keap1/Nrf2 transcriptional pathway and thus production of phase 2 antioxidant enzymes. We used both in vitro and in vivo models. For in vitro studies, we evaluated protective effects of CA on primary neurons exposed to oligomeric Aβ. For in vivo studies, we used two transgenic mouse models of AD, human amyloid precursor protein (hAPP)-J20 mice and triple transgenic (3xTg AD) mice. We treated these mice trans-nasally with CA twice weekly for 3 months. Subsequently, we performed neurobehavioral tests and quantitative immunohistochemistry to assess effects on AD-related phenotypes, including learning and memory, and synaptic damage. In vitro, CA reduced dendritic spine loss in rat neurons exposed to oligomeric Aβ. In vivo, CA treatment of hAPP-J20 mice improved learning and memory in the Morris water maze test. Histologically, CA increased dendritic and synaptic markers, and decreased astrogliosis, Aβ plaque number, and phospho-tau staining in the hippocampus. We conclude that CA exhibits therapeutic benefits in rodent AD models and since the FDA has placed CA on the 'generally regarded as safe' (GRAS) list, thus obviating the need for safety studies, human clinical trials will be greatly expedited.

Introduction: Amputation is a major condition that requires inpatient rehabilitation. Some research has been conducted to explore the risk factors for readmission of patients from inpatient rehabilitation facilities to acute care hospitals. However, few studies have included patients with amputation in the study population. Objective: To identify the risk factors for readmission of patients with amputation to acute care hospitals from an inpatient rehabilitation facility. Design: Retrospective cohort study. Setting: An acute rehabilitation hospital associated with a community‐based tertiary medical center. Patients: A retrospective review of 156 independent admissions of 145 patients from June 2019 to July 2022. Main Outcome Measure: The study outcome measure was readmission to acute care from an acute rehabilitation unit. Results: Of the 156 independent admissions, the readmission rate was 19% (29/156). The most common cause of transfer was incision‐site complications (9/29, 31%), including wound infection and wound dehiscence. Patients with amputation readmitted to acute care are more likely to be receiving dialysis (p <.001), have a longer length of stay in acute care before admission to the rehabilitation facility (p =.039), and have a lower Section GG score on admission (p <.001). Age, sex, ethnicity, amputation level, and history of diabetes mellitus were not associated with acute care hospital readmission. The logistic regression model revealed that patients being on dialysis was the only significant risk factor predictive of readmission to acute care (odds ratio [OR] 4.82, p =.006). Conclusions: This study showed that incision‐site complications were the most common cause of disruption in inpatient rehabilitation via acute hospital readmission in patients with amputation. Being on dialysis was associated with a higher risk of readmission to acute care hospitals. Based on the results of this study, specific rehabilitation plans might be required for patients with amputation who carry certain risk factors to reduce rehospitalization to the acute care unit. [ABSTRACT FROM AUTHOR]

Animal studies have demonstrated the ability of pancreatic acinar cells to transform into pancreatic ductal adenocarcinoma (PDAC). However, the tumorigenic potential of human pancreatic acinar cells remains under debate. To address this gap in knowledge, we expand sorted human acinar cells as 3D organoids and genetically modify them through introduction of common PDAC mutations. The acinar organoids undergo dramatic transcriptional alterations but maintain a recognizable DNA methylation signature. The transcriptomes of acinar organoids are similar to those of disease-specific cell populations. Oncogenic KRAS alone do not transform acinar organoids. However, acinar organoids can form PDAC in vivo after acquiring the four most common driver mutations of this disease. Similarly, sorted ductal cells carrying these genetic mutations can also form PDAC, thus experimentally proving that PDACs can originate from both human acinar and ductal cells. RNA-seq analysis reveal the transcriptional shift from normal acinar cells towards PDACs with enhanced proliferation, metabolic rewiring, down-regulation of MHC molecules, and alterations in the coagulation and complement cascade. By comparing PDAC-like cells with normal pancreas and PDAC samples, we identify a group of genes with elevated expression during early transformation which represent potential early diagnostic biomarkers. The cellular origin of human pancreatic ductal adenocarcinoma (PDAC) is still unclear. Here the authors used human primary acinar and ductal cells to successfully reconstitute PDAC tumorigenesis from both lineages and revealed transcriptional changes during early PDAC progression. [ABSTRACT FROM AUTHOR]