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BackgroundInterventions to define medical jargon have been shown to improve electronic health record (EHR) note comprehension among crowdsourced participants on Amazon Mechanical Turk (AMT). However, AMT participants may not be representative of the general population or patients who are most at-risk for low health literacy. ObjectiveIn this work, we assessed the efficacy of an intervention (NoteAid) for EHR note comprehension among participants in a community hospital setting. MethodsParticipants were recruited from Lowell General Hospital (LGH), a community hospital in Massachusetts, to take the ComprehENotes test, a web-based test of EHR note comprehension. Participants were randomly assigned to control (n=85) or intervention (n=89) groups to take the test without or with NoteAid, respectively. For comparison, we used a sample of 200 participants recruited from AMT to take the ComprehENotes test (100 in the control group and 100 in the intervention group). ResultsA total of 174 participants were recruited from LGH, and 200 participants were recruited from AMT. Participants in both intervention groups (community hospital and AMT) scored significantly higher than participants in the control groups (P

Background Cutaneous immune-related adverse events (cirAEs) are the most common toxicities to occur in the setting of immune checkpoint inhibitor (ICI) therapy. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. Objectives To investigate the influence of cancer type and histology on the development of cirAEs in the setting of ICI therapy and survival outcomes. Methods This retrospective cohort study included patients recruited between 1 December 2011 and 30 October 2020. They received ICI from 2011 to 2020 with follow-up of outcomes through October 2021. We identified 3668 recipients of ICI therapy who were seen at Massachusetts General Brigham and Dana-Farber. Of these, 669 developed cirAEs. Records that were incomplete or categories of insufficient sample size were excluded from the study cohort. Multivariate Cox proportional hazards models were used to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI initiation, and year of ICI initiation. Time-varying Cox proportional hazards modelling was used to examine the impact of cirAE development on mortality. Results Compared with other nonepithelial cancers (neuroendocrine, leukaemia, lymphoma, myeloma, sarcoma and central nervous system malignancies), cutaneous squamous cell carcinoma [cSCC; hazard ratio (HR) 3.57, P < 0.001], melanoma (HR 2.09, P < 0.001), head and neck adenocarcinoma (HR 2.13, P = 0.009), genitourinary transitional cell carcinoma (HR 2.15, P < 0.001) and genitourinary adenocarcinoma (HR 1.53, P = 0.037) were at significantly higher risk of cirAEs in multivariate analyses. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma (HR 0.37, P < 0.001) and cSCC (HR 0.51, P = 0.011). Conclusions The highest rate of cirAEs and subsequent survival benefits were observed in cutaneous malignancies treated with ICI therapies. This study improves our understanding of patients who are at highest risk of developing cirAEs and would, therefore, benefit from appropriate counselling and closer monitoring by their oncologists and dermatologists throughout their ICI therapy. Limitations include its retrospective nature and cohort from one geography. [ABSTRACT FROM AUTHOR]

Despite the prevalence of pericytes in the microvasculature of the heart, their role during ischemia-induced remodeling remains unclear. We used multiple lineage-tracing mouse models and found that pericytes migrated to the injury site and expressed profibrotic genes, coinciding with increased vessel leakage after myocardial infarction (MI). Single- cell RNA- Seq of cardiac pericytes at various time points after MI revealed the temporally regulated induction of genes related to vascular permeability, extracellular matrix production, basement membrane degradation, and TGF-[beta] signaling. Deleting TGF- [beta] receptor 1 in chondroitin sulfate proteoglycan 4-expressing (Cspg4-expressing) cells reduced fibrosis following MI, leading to a transient improvement in the cardiac ejection fraction. Furthermore, genetic ablation of Cspg4-expressing cells resulted in excessive vascular permeability, a decline in cardiac function, and increased mortality in the second week after MI. These data reveal an essential role for cardiac pericytes in the control of vascular homeostasis and the fibrotic response after acute ischemic injury, information that will help guide the development of novel strategies to preserve vascular integrity and attenuate pathological cardiac remodeling., Introduction Injury to the adult mammalian heart results in irreversible loss of cardiomyocytes and triggers an inflammatory cascade that forms a collagen-rich scar. A significant component of fibrosis following myocardial [...]

Activity‐regulated gene (ARG) expression patterns in the hippocampus (HPC) regulate synaptic plasticity, learning, and memory, and are linked to both risk and treatment responses for many neuropsychiatric disorders. The HPC contains discrete classes of neurons with specialized functions, but cell type‐specific activity‐regulated transcriptional programs are not well characterized. Here, we used single‐nucleus RNA‐sequencing (snRNA‐seq) in a mouse model of acute electroconvulsive seizures (ECS) to identify cell type‐specific molecular signatures associated with induced activity in HPC neurons. We used unsupervised clustering and a priori marker genes to computationally annotate 15,990 high‐quality HPC neuronal nuclei from N = 4 mice across all major HPC subregions and neuron types. Activity‐induced transcriptomic responses were divergent across neuron populations, with dentate granule cells being particularly responsive to activity. Differential expression analysis identified both upregulated and downregulated cell type‐specific gene sets in neurons following ECS. Within these gene sets, we identified enrichment of pathways associated with varying biological processes such as synapse organization, cellular signaling, and transcriptional regulation. Finally, we used matrix factorization to reveal continuous gene expression patterns differentially associated with cell type, ECS, and biological processes. This work provides a rich resource for interrogating activity‐regulated transcriptional responses in HPC neurons at single‐nuclei resolution in the context of ECS, which can provide biological insight into the roles of defined neuronal subtypes in HPC function. [ABSTRACT FROM AUTHOR]

RPGR mutations are the most common cause of X-linked retinitis pigmentosa (XLRP). High myopia has been described as a very frequent feature among affected female carriers of XLRP. However, the clinical phenotype of female patients presenting with X-linked RPGR-related high myopia has not been well described. Retrospective case series of four female patients with RPGR mutations and a diagnosis of high myopia, who presented to two academic eye centers. Clinical data, including age, family history, visual acuity, refractive error, dilated fundus exam, fundus photography, optical coherence tomography, electroretinography, and results of genetic testing, were collected. Three RPGR variants identified in the present study have not been previously associated with myopia in female carriers. One variant (c.2405_2406delAG, p.Glu802Glyfs *32) has been previously associated with a myopic phenotype in a female patient. Patients became symptomatic between the first and sixth decades of life. Myopia-associated tilted optic discs and posterior staphyloma were present in all patients. Two patients presented with intraretinal migration of the retinal pigment epithelium. RPGR-related high myopia has been associated with mutations in exons 1–14 and ORF15 in heterozygous females. There is a wide range of visual function among carriers. Although the exact mechanism of RPGR-related high myopia is still unclear, continued molecular diagnosis and description of phenotypes remain a crucial step in understanding the impact of RPGR mutations on visual function in female XLRP carriers. [ABSTRACT FROM AUTHOR]

The rising global prevalence of myopia is a growing concern for clinicians, as it predisposes patients to severe ocular pathologies including glaucoma. High myopia can be associated with clinical features that resemble glaucomatous damage, which make an accurate glaucoma diagnosis challenging, particularly among patients with normal intraocular pressures. These patients may also present with established visual field defects which can mimic glaucoma, and standard imaging technology is less useful in disease detection and monitoring due to the lack of normative data for these anatomically unique eyes. Progression over time remains the most critical factor in facilitating the detection of early glaucomatous changes, and thus careful longitudinal follow-up of high-risk myopic patients is the most important aspect of management. Here, we review our current understanding of the complex relationship between myopia and glaucoma, and the diagnostic challenges and limitations of current testing protocols including visual field, intraocular pressure, and imaging. Furthermore, we discuss the clinical findings of two highly myopic patients with suspected glaucoma. [ABSTRACT FROM AUTHOR]

Objectives. Primary cilia are conserved organelles found in polarized mammalian cells that regulate neuronal growth, migration, and differentiation. Proper cilia formation is essential during eye development. Our previous reports found that both amacrine and retinal ganglion cells (RGCs) contain primary cilia in primate and rodent retinas. However, whether primary cilia are present in the inner retina of human retinal organoids remains unknown. The purpose of this study is to characterize the primary cilia distribution in human embryonic stem cell (hESC-derived retinal organoid development. Materials and Methods. Retinal organoids were differentiated from a hESC line, harvested at various developmental timepoints (day 44-day 266), and immunostained with antibodies for primary cilia, including Arl13b (for the axoneme), AC3, and Centrin3 (for the basal body). AP2α, Prox1, GAD67, Calretinin, GFAP, PKCα, and Chx10 antibodies as well as Brn3b-promoted tdTomato expression were used to visualize retinal cell types. Results. A group of ciliated cells were present in the inner aspects of retinal organoids from day 44 to day 266 in culture. Ciliated Chx10-positive retinal progenitor cells, GFAP-positive astrocytes, and PKCα-positive rod-bipolar cells were detected later during development (day 176 to day 266). Ciliation persisted during all stages of retinal developmental in AP2α-positive amacrine cells, but it was decreased in Brn3b-positive retinal ganglion cells (RGCs) at later time points. Additionally, AC3-positive astrocytes significantly decreased during the later stages of organoid formation. Conclusions. Amacrine cells in retinal organoids retain cilia throughout development, whereas RGC ciliation gradually and progressively decreases with organoid maturation. [ABSTRACT FROM AUTHOR]

Neurons derived from human induced pluripotent stem cells (hiPSCs) have been used to model basic cellular aspects of neuropsychiatric disorders, but the relationship between the emergent phenotypes and the clinical characteristics of donor individuals has been unclear. We analyzed RNA expression and indices of cellular function in hiPSC-derived neural progenitors and cortical neurons generated from 13 individuals with high polygenic risk scores (PRSs) for schizophrenia (SCZ) and a clinical diagnosis of SCZ, along with 15 neurotypical individuals with low PRS. We identified electrophysiological measures in the patient-derived neurons that implicated altered Na+ channel function, action potential interspike interval, and gamma-aminobutyric acid-ergic neurotransmission. Importantly, electrophysiological measures predicted cardinal clinical and cognitive features found in these SCZ patients. The identification of basic neuronal physiological properties related to core clinical characteristics of illness is a potentially critical step in generating leads for novel therapeutics. [ABSTRACT FROM AUTHOR]

Recent advances in optogenetics hold promise for vision restoration in degenerative eye diseases. Optogenetics refers to techniques that use light to control the cellular activity of targeted cells. Although optogenetics is a relatively new technology, multiple therapeutic options are already being explored in pre-clinical and phase I/II clinical trials with the aim of developing novel, safe, and effective treatments for major blinding eye diseases, such as glaucoma and retinitis pigmentosa. Optogenetic approaches to visual restoration are primarily aimed at replacing lost or dysfunctional photoreceptors by inserting light-sensitive proteins into downstream retinal neurons that have no intrinsic light sensitivity. Such approaches are attractive because they are agnostic to the genetic causes of retinal degeneration, which raises hopes that all forms of retinal dystrophic and degenerative diseases could become treatable. Optogenetic strategies can also have a far-reaching impact on translational research by serving as important tools to study the pathogenesis of retinal degeneration and to identify clinically relevant therapeutic targets. For example, the CRY-CIBN optogenetic system has been recently applied to animal models of glaucoma, suggesting a potential role of OCRL in the regulation of intraocular pressure in trabecular meshwork. As optogenetic strategies are being intensely investigated, it appears crucial to consider the opportunities and challenges such therapies may offer. Here, we review the more recent promising optogenetic molecules, vectors, and applications of optogenetics for the treatment of retinal degeneration and glaucoma. We also summarize the preliminary results of ongoing clinical trials for visual restoration. [ABSTRACT FROM AUTHOR]

Single-cell gene expression technologies are powerful tools to study cell types in the human brain, but efforts have largely focused on cortical brain regions. We therefore created a single-nucleus RNA-sequencing resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions that serve as key nodes of the human brain reward circuitry: nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, and dorsolateral prefrontal cortex. We first identified novel subpopulations of interneurons and medium spiny neurons (MSNs) in the nucleus accumbens and further characterized robust GABAergic inhibitory cell populations in the amygdala. Joint analyses across the 107 reported cell classes revealed cell-type substructure and unique patterns of transcriptomic dynamics. We identified discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens to which we mapped cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction. [Display omitted] • snRNA sequencing (70,615 nuclei) of 5 human brain regions with roles in reward • Characterization of the transcriptomic architecture across 107 cell classes • Genetic risk association for substance use phenotypes in specific cell populations • Interactive app for each brain region to explore genes of interest in cell classes For this NeuroResource, >100 cell classes from five brain regions in the human reward circuitry are characterized by single-nucleus RNA sequencing, with interactive apps made available. The molecular relationships across this circuitry are described, and genetic risk for various psychiatric and substance use phenotypes is quantified across all cell classes. [ABSTRACT FROM AUTHOR]

Summary Memories are thought to be sparsely encoded in neuronal networks, but little is known about why a given neuron is recruited or allocated to a particular memory trace. Previous research shows that in the lateral amygdala (LA), neurons with increased CREB are selectively recruited to a fear memory trace. CREB is a ubiquitous transcription factor implicated in many cellular processes. Which process mediates neuronal memory allocation? One hypothesis is that CREB increases neuronal excitability to bias neuronal recruitment, although this has not been shown experimentally. Here we use several methods to increase neuronal excitability and show this both biases recruitment into the memory trace and enhances memory formation. Moreover, artificial activation of these neurons alone is a sufficient retrieval cue for fear memory expression, showing that these neurons are critical components of the memory trace. These results indicate that neuronal memory allocation is based on relative neuronal excitability immediately before training. Video Abstract [ABSTRACT FROM AUTHOR]

Autophagy is a fundamental catabolic process whereby excessive or damaged cytoplasmic components are degraded through lysosomes to maintain cellular homeostasis. Studies of mTOR signaling have revealed that mTOR controls biomass generation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Primary cilia, the assembly of which depends on kinesin molecular motors, serve as sensory organelles and signaling platforms. Given these pathways' central role in maintaining cellular and physiological homeostasis, a connection between mTOR and primary cilia signaling is starting to emerge in a variety of diseases. In this review, we highlight recent advances in our understanding of the complex crosstalk between the mTOR pathway and cilia and discuss its function in the context of related diseases., (Copyright © 2023. Published by Elsevier Inc.)

Objective: To determine whether a pharmacistled intervention would increase the number of naloxone prescriptions and naloxone administration education in a primary care family medicine setting., Design: Prospective quality improvement intervention in an academic family medicine clinic., Methods: We surveyed providers about naloxone knowledge, prescribing habits, and prescribing barriers. We identified patients on chronic opioid therapy, through electronic health records for the year 2019. Overdose risk categories based upon morphine milligram equivalent doses and concomitant benzodiazepine use were used to determine patients who met criteria for naloxone. Pharmacists phoned qualified patients to discuss overdose risk and naloxone benefits. Patients who accepted naloxone prescriptions used their local pharmacy through a department-approved standing order set., Results: From the survey results, there were 47 of 54 provider responses, and the majority noted that they do not routinely prescribe naloxone in high-risk patients. The predominant barriers were lack of time during visit and naloxone administration education. The population of patients from chart review included 93 high-risk patients with a mean age of 58 years. During the time of intervention, 71 patients remained eligible for naloxone coprescribing. Of the patients contacted, 29 (40 percent) accepted the intervention prescription, and subsequently, 22 picked up their prescription from the pharmacy. Sixteen received counseling with a support person. Twelve patients had naloxone already at home, and two received counseling with a support person., Conclusion: The naloxone prescribing intervention is achievable. The results of this intervention support identifying patients at increased risk of opioid overdose and offer education of a support person for naloxone in a large academic family medicine clinic.

Cigarette smoking is undoubtedly the single most important risk factor and trigger for vasospastic angina, a condition also known as Prinzmetal angina secondary to coronary artery vasospasm. Even decades before vasospastic angina was first described by Dr. Myron Prinzmetal and his colleagues in 1959, there had been suspected connections between smoking and coronary artery vasospasm in what was alluded to then as "tobacco angina." The intimate relationship between smoking and vasospastic angina has since been extensively researched and validated through decades of epidemiological and clinical studies. The fact that smoking would aggravate vasospastic angina comes with very little surprise, as it has been shown to adversely impact many of the disease processes thought to underlie vasospastic angina, including autonomic dysfunction, endothelial dysfunction, smooth muscle hyperactivity, and genetic susceptibility. While avoidance of smoking is the first logical step in managing smokers with vasospastic angina, there have been reported cases of vasospastic angina paradoxically triggered by smoking cessation or relieved with smoking resumption or nicotine replacement therapy. Thus, there appears to be patient-specific factors that could significantly alter the close connection between smoking and vasospastic angina, warranting further mechanistic investigations. In this review, we will examine this complicated relationship between smoking and vasospastic angina from multiple perspectives (historical, mechanistic, and clinical) and call attention to the "smoking paradox," which, with further elucidation, may provide additional insight into the complex mechanisms of VSA and potentially new strategies to treat medically refractory VSA, at least in selected individuals., Competing Interests: CONFLICT OF INTEREST There are no conflicts of interest.

Sesamoid bones and accessory ossicles are common incidental findings on radiographs. These can occasionally become symptomatic, usually after a precipitating event such as an injury or overuse, or they can be incidental findings unrelated to the presenting pathology. The aim of this study was to highlight a rare case of a bipartite fifth metatarsal sesamoid bone and to review previous literature regarding sesamoid bones and accessory ossicles.

Following learning, increased coupling between spindle oscillations in the medial prefrontal cortex (mPFC) and ripple oscillations in the hippocampus is thought to underlie memory consolidation. However, whether learning-induced increases in ripple-spindle coupling are necessary for successful memory consolidation has not been tested directly. In order to decouple ripple-spindle oscillations, here we chemogenetically inhibited parvalbumin-positive (PV + ) interneurons, since their activity is important for regulating the timing of spiking activity during oscillations. We found that contextual fear conditioning increased ripple-spindle coupling in mice. However, inhibition of PV + cells in either CA1 or mPFC eliminated this learning-induced increase in ripple-spindle coupling without affecting ripple or spindle incidence. Consistent with the hypothesized importance of ripple-spindle coupling in memory consolidation, post-training inhibition of PV + cells disrupted contextual fear memory consolidation. These results indicate that successful memory consolidation requires coherent hippocampal-neocortical communication mediated by PV + cells.

Anxiety is an adaptive response to potentially threatening situations. Exaggerated and uncontrolled anxiety responses become maladaptive and lead to anxiety disorders. Anxiety is shaped by a network of forebrain structures, including the hippocampus, septum, and prefrontal cortex. In particular, neural inputs arising from the ventral hippocampus (vHPC) to the lateral septum (LS) and medial prefrontal cortex (mPFC) are thought to serve as principal components of the anxiety circuit. However, the role of vHPC-to-LS and vHPC-to-mPFC signals in anxiety is unclear, as no study has directly compared their behavioral contribution at circuit level. We targeted LS-projecting vHPC cells and mPFC-projecting vHPC cells by injecting the retrogradely propagating canine adenovirus encoding Cre recombinase into the LS or mPFC, and injecting a Cre-responsive AAV (AAV8-hSyn-FLEX-hM3D or hM4D) into the vHPC. Consequences of manipulating these neurons were examined in well-established tests of anxiety. Chemogenetic manipulation of LS-projecting vHPC cells led to bidirectional changes in anxiety: activation of LS-projecting vHPC cells decreased anxiety whereas inhibition of these cells produced opposite anxiety-promoting effects. The observed anxiety-reducing function of LS-projecting cells was in contrast with the function of mPFC-projecting cells, which promoted anxiety. In addition, double retrograde tracing demonstrated that LS- and mPFC-projecting cells represent two largely anatomically distinct cell groups. Altogether, our findings suggest that the vHPC houses discrete populations of cells that either promote or suppress anxiety through differences in their projection targets. Disruption of the intricate balance in the activity of these two neuron populations may drive inappropriate behavioral responses seen in anxiety disorders.