A Neurosurgical Readmissions Reduction Program in an Academic Hospital Leveraging Machine Learning, Workflow Analysis, and Simulation.

BACKGROUND: Predicting 30-day hospital readmissions is crucial for improving patient outcomes, optimizing resource allocation, and achieving financial savings. Existing studies reporting the development of machine learning (ML) models predictive of neurosurgical readmissions do not report factors related to clinical implementation. OBJECTIVES: Train individual predictive models with good performance (area under the receiver operating characteristic curve or AUROC > 0.8), identify potential interventions through semi-structured interviews, and demonstrate estimated clinical and financial impact of these models. METHODS: Electronic health records were utilized with five ML methodologies: gradient boosting, decision tree, random forest, ridge logistic regression, and linear support vector machine. Variables of interest were determined by domain experts and literature. The dataset was split divided 80% for training and validation and 20% for testing randomly. Clinical workflow analysis was conducted using semi-structured interviews to identify possible intervention points. Calibrated agent-based models (ABMs), based on a previous study with interventions, were applied to simulate reductions of the 30-day readmission rate and financial costs. RESULTS: The dataset covered 12,334 neurosurgical intensive care unit (NSICU) admissions (11,029 patients); 1,903 spine surgery admissions (1,641 patients), and 2,208 traumatic brain injury (TBI) admissions (2,185 patients), with readmission rate of 13.13, 13.93, and 23.73%, respectively. The random forest model for NSICU achieved best performance with an AUROC score of 0.89, capturing potential patients effectively. Six interventions were identified through 12 semi-structured interviews targeting preoperative, inpatient stay, discharge phases, and follow-up phases. Calibrated ABMs simulated median readmission reduction rates and resulted in 13.13 to 10.12% (NSICU), 13.90 to 10.98% (spine surgery), and 23.64 to 21.20% (TBI). Approximately $1,300,614.28 in saving resulted from potential interventions. CONCLUSION: This study reports the successful development and simulation of an ML-based approach for predicting and reducing 30-day hospital readmissions in neurosurgery. The intervention shows feasibility in improving patient outcomes and reducing financial losses.

RIT2 regulates autophagy lysosomal pathway induction and protects against α-synuclein pathology in a cellular model of Parkinson's disease.

Substantial work has been devoted to better understand the contribution of the myriad of genes that may underly the development of Parkinson's disease (PD) and their role in disease etiology. The small GTPase Ras-like without CAAX2 (RIT2) is one such genetic risk factor, with one single nucleotide polymorphism in the RIT2 locus, rs12456492, having been associated with PD risk in multiple populations. While RIT2 has previously been shown to influence signaling pathways, dopamine transporter trafficking, and LRRK2 activity, its cellular function remains unclear. In the current study, we have situated RIT2 to be upstream of various diverse processes associated with PD. In cellular models, we have shown that RIT2 is necessary for activity-dependent changes in the expression of genes related to the autophagy-lysosomal pathway (ALP) by regulating the nuclear translocation of MiT/TFE3-family transcription factors. RIT2 is also associated with lysosomes and can regulate autophagic flux and clearance by regulating lysosomal hydrolase expression and activity. Interestingly, upregulation of RIT2 can augment ALP flux and protect against α-synuclein aggregation in cortical neurons. Taken together, the present study suggests that RIT2 can regulates gene expression upstream of ALP function and that enhancing RIT2 activity may provide therapeutic benefit in PD.

Sleep Patterns of Premedical Undergraduate Students: Pilot Study and Protocol Evaluation.

BACKGROUND: Poor sleep hygiene persists in college students today, despite its heavy implications on adolescent development and academic performance. Although sleep patterns in undergraduates have been broadly investigated, no study has exclusively assessed the sleep patterns of premedical undergraduate students. A gap also exists in the knowledge of how students perceive their sleep patterns compared to their actual sleep patterns. OBJECTIVE: This study aims to address 2 research questions: What are the sleep patterns of premedical undergraduate students? Would the proposed study protocol be feasible to examine the perception of sleep quality and promote sleep behavioral changes in premedical undergraduate students? METHODS: An anonymous survey was conducted with premedical students in the Medical Science Baccalaureate program at an R1: doctoral university in the Midwest United States to investigate their sleep habits and understand their demographics. The survey consisted of both Pittsburg Sleep Quality Index (PSQI) questionnaire items (1-9) and participant demographic questions. To examine the proposed protocol feasibility, we recruited 5 students from the survey pool for addressing the perception of sleep quality and changes. These participants followed a 2-week protocol wearing Fitbit Inspire 2 watches and underwent preassessments, midassessments, and postassessments. Participants completed daily reflections and semistructured interviews along with PSQI questionnaires during assessments. RESULTS: According to 103 survey responses, premedical students slept an average of 7.1 hours per night. Only a quarter (26/103) of the participants experienced good sleep quality (PSQI<5), although there was no significant difference (P=.11) in the proportions of good (PSQI<5) versus poor sleepers (PSQI≥5) across cohorts. When students perceived no problem at all in their sleep quality, 50% (14/28) of them actually had poor sleep quality. Among the larger proportion of students who perceived sleep quality as only a slight problem, 26% (11/43) of them presented poor sleep quality. High stress levels were associated with poor sleep quality. This study reveals Fitbit as a beneficial tool in raising sleep awareness. Participants highlighted Fitbit elements that aid in comprehension such as being able to visualize their sleep stage breakdown and receive an overview of their sleep pattern by simply looking at their Fitbit sleep scores. In terms of protocol evaluation, participants believed that assessments were conducted within the expected duration, and they did not have a strong opinion about the frequency of survey administration. However, Fitbit was found to provide notable variation daily, leading to missing data. Moreover, the Fitbit app's feature description was vague and could lead to confusion. CONCLUSIONS: Poor sleep quality experienced by unaware premedical students points to a need for raising sleep awareness and developing effective interventions. Future work should refine our study protocol based on lessons learned and health behavior theories and use Fitbit as an informatics solution to promote healthy sleep behaviors.

Improving the design of patient-generated health data visualizations: design considerations from a Fitbit sleep study.

Interactive data visualization can be a viable way to discover patterns in patient-generated health data and enable health behavior changes. However, very few studies have investigated the design and usability of such data visualization. The present study aimed to (1) explore user experiences with sleep data visualizations in the Fitbit app, and (2) focus on end users' perspectives to identify areas of improvement and potential solutions. The study recruited eighteen pre-medicine college students, who wore Fitbit watches for a two-week sleep data collection period and participated in an exit semi-structured interview to share their experience. A focus group was conducted subsequently to ideate potential solutions. The qualitative analysis identified six pain points (PPs) from the interview data using affinity mapping. Four design solutions were proposed by the focus group to address these PPs and illustrated by a set of mock-ups. The study findings informed four design considerations: (1) usability, (2) transparency and explainability, (3) understandability and actionability, and (4) individualized benchmarking. Further research is needed to examine the design guidelines and best practices of sleep data visualization, to create well-designed visualizations for the general population that enables health behavior changes.

User-Centered Evaluation and Design Recommendations for an Internal Medicine Resident Competency Assessment Dashboard.

OBJECTIVES: Clinical Competency Committee (CCC) members employ varied approaches to the review process. This makes the design of a competency assessment dashboard that fits the needs of all members difficult. This work details a user-centered evaluation of a dashboard currently utilized by the Internal Medicine Clinical Competency Committee (IM CCC) at the University of Cincinnati College of Medicine and generated design recommendations. METHODS: Eleven members of the IM CCC participated in semistructured interviews with the research team. These interviews were recorded and transcribed for analysis. The three design research methods used in this study included process mapping (workflow diagrams), affinity diagramming, and a ranking experiment. RESULTS: Through affinity diagramming, the research team identified and organized opportunities for improvement about the current system expressed by study participants. These areas include a time-consuming preprocessing step, lack of integration of data from multiple sources, and different workflows for each step in the review process. Finally, the research team categorized nine dashboard components based on rankings provided by the participants. CONCLUSION: We successfully conducted user-centered evaluation of an IM CCC dashboard and generated four recommendations. Programs should integrate quantitative and qualitative feedback, create multiple views to display these data based on user roles, work with designers to create a usable, interpretable dashboard, and develop a strong informatics pipeline to manage the system. To our knowledge, this type of user-centered evaluation has rarely been attempted in the medical education domain. Therefore, this study provides best practices for other residency programs to evaluate current competency assessment tools and to develop new ones.

Roles of Endomembrane Alkali Cation/Proton Exchangers in Synaptic Function and Neurodevelopmental Disorders.

Endomembrane alkali cation (Na+, K+)/proton (H+) exchangers (eNHEs) are increasingly associated with neurological disorders. These eNHEs play integral roles in regulating the luminal pH, processing, and trafficking of cargo along the secretory (Golgi and post-Golgi vesicles) and endocytic (early, recycling, and late endosomes) pathways, essential regulatory processes vital for neuronal development and plasticity. Given the complex morphology and compartmentalization of multipolar neurons, the contribution of eNHEs in maintaining optimal pH homeostasis and cargo trafficking is especially significant during periods of structural and functional development and remodeling. While the importance of eNHEs has been demonstrated in a variety of non-neuronal cell types, their involvement in neuronal function is less well understood. In this review, we will discuss their emerging roles in excitatory synaptic function, particularly as it pertains to cellular learning and remodeling. We will also explore their connections to neurodevelopmental conditions, including intellectual disability, autism, and attention deficit hyperactivity disorders.

Inside the Insulin Secretory Granule.

The pancreatic ß-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the bloodstream. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules (SGs), and these specialized organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin. Insulin is synthesized in the endoplasmic reticulum (ER) as a biologically inactive precursor, proinsulin, along with several other proteins that will also become members of the insulin SG. Their coordinated synthesis enables synchronized transit through the ER and Golgi apparatus for congregation at the trans-Golgi network, the initiating site of SG biogenesis. Here, proinsulin and its constituents enter the SG where conditions are optimized for proinsulin processing into insulin and subsequent insulin storage. A healthy ß-cell is continually generating SGs to supply insulin in vast excess to what is secreted. Conversely, in type 2 diabetes (T2D), the inability of failing ß-cells to secrete may be due to the limited biosynthesis of new insulin. Factors that drive the formation and maturation of SGs and thus the production of insulin are therefore critical for systemic glucose control. Here, we detail the formative hours of the insulin SG from the luminal perspective. We do this by mapping the journey of individual members of the SG as they contribute to its genesis.

Off-target effect of the BMI1 inhibitor PTC596 drives epithelial-mesenchymal transition in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is an incurable primary brain tumor containing a sub-population of cancer stem cells (CSCs). Polycomb Repressive Complex (PRC) proteins BMI1 and EZH2 are enriched in CSCs, promoting clonogenic growth and resistance to genotoxic therapies. We report here that when used at appropriate concentrations, pharmaceutical inhibitors of BMI1 could efficiently prevent GBM colony growth and CSC self-renewal in vitro and significantly extend lifespan in terminally ill tumor-bearing mice. Notably, molecular analyses revealed that the commonly used PTC596 molecule targeted both BMI1 and EZH2, possibly providing beneficial therapeutic effects in some contexts. On the other hand, treatment with PTC596 resulted in instant reactivation of EZH2 target genes and induction of a molecular program of epithelial-mesenchymal transition (EMT), possibly explaining the modified phenotype of some PTC596-treated tumors. Treatment with a related but more specific BMI1 inhibitor resulted in tumor regression and maintenance of cell identity. We conclude that inhibition of BMI1 alone is efficient at inducing GBM regression, and that dual inhibition of BMI1 and EZH2 using PTC596 may be also beneficial but only in specific contexts.

A Christianson syndrome-linked deletion mutation (Δ287ES288) in SLC9A6 impairs hippocampal neuronal plasticity.

Christianson Syndrome is a rare but increasingly diagnosed X-linked intellectual disability disorder that arises from mutations in SLC9A6/NHE6, a pH-regulating transporter that localizes to early and recycling endosomes. We have recently reported that one of the originally identified disease-causing mutations in NHE6 (p.E287-S288del, or ΔES) resulted in a loss of its pH regulatory function. However, the impact of this mutation upon neuronal synapse formation and plasticity is unknown. Here, we investigate the consequences of the ΔES mutant upon mouse hippocampal pyramidal neurons by expressing a fluorescently-labeled ΔES NHE6 construct into primary hippocampal neurons. Neurons expressing the ΔES mutant showed significant reductions in mature dendritic spine density with a concurrent increase in immature filopodia. Furthermore, compared to wild-type (WT), ΔES-containing endosomes are redirected away from early and recycling endosomes toward lysosomes. In parallel, the ΔES mutant reduced the trafficking of glutamatergic AMPA receptors to excitatory synapses and increased their accumulation within lysosomes for potential degradation. Upon long-term potentiation (LTP), neurons expressing ΔES failed to undergo significant structural and functional changes as observed in controls and WT transfectants. Interestingly, synapse density and LTP-induced synaptic remodeling in ΔES-expressing neurons were partially restored by bafilomycin, a vesicular alkalinisation agent, or by leupeptin, an inhibitor of lysosomal proteolytic degradation. Overall, our results demonstrate that the ∆ES mutation attenuates synapse density and structural and functional plasticity in hippocampal neurons. These deficits may be partially due to the mistargeting of AMPA receptors and other cargos to lysosomes, thereby preventing their trafficking during synaptic remodeling. This mechanism may contribute to the cognitive learning deficits observed in patients with Christianson Syndrome and suggests a potential therapeutic strategy for treatment.

Generalizing Duchenne to sad expressions with binocular rivalry and perception ratings.

Discrete emotion theories emphasize the modularity of facial expressions, while functionalist theories suggest that a single facial action may have a common meaning across expressions. Smiles involving the Duchenne marker, eye constriction causing crow's feet, are perceived as intensely positive and sincere. To test whether the Duchenne marker is a general index of intensity and sincerity, we contrasted positive and negative expressions with and without the Duchenne marker in a binocular rivalry paradigm. Both smiles and sad expressions involving the Duchenne marker were perceived longer than non-Duchenne expressions, and participants rated all Duchenne expressions as more affectively intense and more sincere than their non-Duchenne counterparts. Correlations between perceptual dominance and ratings suggested that the Duchenne marker increased the dominance of smiles and sad expressions by increasing their perceived affective intensity. The results provide evidence in favor of Darwin's hypothesis that specific facial actions have a general function (conveying affect intensification and sincerity) across expressions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A potential gain-of-function variant of SLC9A6 leads to endosomal alkalinization and neuronal atrophy associated with Christianson Syndrome.

Loss-of-function mutations in the recycling endosomal (Na+,K+)/H+ exchanger gene SLC9A6/NHE6 result in overacidification and dysfunction of endosomal-lysosomal compartments, and cause a neurodevelopmental and degenerative form of X-linked intellectual disability called Christianson Syndrome (CS). However, knowledge of the disease heterogeneity of CS is limited. Here, we describe the clinical features and underlying molecular and cellular mechanisms associated with a CS patient carrying a de novo missense variant (p.Gly218Arg; G218R) of a conserved residue in its ion translocation domain that results in a potential gain-of-function. The patient manifested several core symptoms typical of CS, including pronounced cognitive impairment, mutism, epilepsy, ataxia and microcephaly; however, deterioration of motor function often observed after the first decade of life in CS children with total loss of SLC9A6/NHE6 function was not evident. In transfected non-neuronal cells, complex glycosylation and half-life of the G218R were significantly decreased compared to the wild-type transporter. This correlated with elevated ubiquitination and partial proteasomal-mediated proteolysis of G218R. However, a major fraction was delivered to the plasma membrane and endocytic pathways. Compared to wild-type, G218R-containing endosomes were atypically alkaline and showed impaired uptake of recycling endosomal cargo. Moreover, instead of accumulating in recycling endosomes, G218R was redirected to multivesicular bodies/late endosomes and ejected extracellularly in exosomes rather than progressing to lysosomes for degradation. Attenuated acidification and trafficking of G218R-containing endosomes were also observed in transfected hippocampal neurons, and correlated with diminished dendritic branching and density of mature mushroom-shaped spines and increased appearance of filopodia-like protrusions. Collectively, these findings expand our understanding of the genetic diversity of CS and further elucidate a critical role for SLC9A6/NHE6 in fine-tuning recycling endosomal pH and cargo trafficking, processes crucial for the maintenance of neuronal polarity and mature synaptic structures.

Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome.

Previous findings showed that in mice, complete knockout of activity-dependent neuroprotective protein (ADNP) abolishes brain formation, while haploinsufficiency (Adnp+/-) causes cognitive impairments. We hypothesized that mutations in ADNP lead to a developmental/autistic syndrome in children. Indeed, recent phenotypic characterization of children harboring ADNP mutations (ADNP syndrome children) revealed global developmental delays and intellectual disabilities, including speech and motor dysfunctions. Mechanistically, ADNP includes a SIP motif embedded in the ADNP-derived snippet drug candidate NAP (NAPVSIPQ, also known as CP201), which binds to microtubule end-binding protein 3, essential for dendritic spine formation. Here, we established a unique neuronal membrane-tagged, GFP-expressing Adnp+/- mouse line allowing in vivo synaptic pathology quantification. We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment. Adnp+/-mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal). In conclusion, we have connected ADNP-related synaptic pathology to developmental and behavioral outcomes, establishing NAP in vivo target engagement and identifying potential biomarkers. Together, these studies pave a path toward the clinical development of NAP (CP201) for the treatment of ADNP syndrome.

A Christianson syndrome-linked deletion mutation (∆(287)ES(288)) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death.

BACKGROUND: Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail. METHODS: Here, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu(287) and Ser(288) (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability. RESULTS: In the cell lines, immunoblot analyses showed that the nascent mutant protein was properly synthesized and assembled as a homodimer, but its oligosaccharide maturation and half-life were markedly reduced compared to wild-type (WT) and correlated with enhanced ubiquitination leading to both proteasomal and lysosomal degradation. Despite this instability, a measurable fraction of the transporter was correctly sorted to the plasma membrane. However, the rates of clathrin-mediated endocytosis of the ∆ES mutant as well as uptake of companion vesicular cargo, such as the ligand-bound transferrin receptor, were significantly reduced and correlated with excessive endosomal acidification. Notably, ectopic expression of ∆ES but not WT induced apoptosis when examined in AP-1 cells. Similarly, in transfected primary cultures of mouse hippocampal neurons, membrane trafficking of the ∆ES mutant was impaired and elicited marked reductions in total dendritic length, area and arborization, and triggered apoptotic cell death. CONCLUSIONS: These results suggest that loss-of-function mutations in NHE6 disrupt recycling endosomal function and trafficking of cargo which ultimately leads to neuronal degeneration and cell death in Christianson Syndrome.

Synthesis of carbon-11-labeled aminoalkylindole derivatives as new candidates of cannabinoid receptor radioligands for PET imaging of alcohol abuse.

Carbon-11-labeled aminoalkylindole derivatives (1-butyl-7-[(11)C]methoxy-1H-indol-3-yl)(naphthalene-1-yl)methanone ([(11)C]3), 1-butyl-7-[(11)C]methoxy-3-(naphthalene-1-ylmethyl)-1H-indole ([(11)C]5), and 1-butyl-7-[(11)C]methoxy-3-(naphthalene-2-yl)-1H-indole ([(11)C]8) were prepared by O-[(11)C]methylation of their corresponding precursors with [(11)C]CH3OTf under basic condition (2N NaOH) and isolated by a simplified solid-phase extraction (SPE) method in 50-60% radiochemical yields based on [(11)C]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185-555 GBq/µmol.

Simple synthesis of new carbon-11-labeled 1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives for PET imaging of A3 adenosine receptor.

The reference standards 4a-b, 6a-b, 7a-c, and desmethylated precursors 9a-b, 10a-b, 8a-c were synthesized from 4-methoxyaniline, ethyl 2-chloro-acetoacetate and substituted benzene-1,2-diamines with 3, 5, 6 steps in 61-67%, 34-41%, 23-31%, and with 4, 6, 7 steps in 49-57%, 28-35%, 20-27% overall chemical yield, respectively. The target tracers [(11)C]4a-b, [(11)C]6a-b, [(11)C]7a-c were synthesized from their corresponding precursors with [(11)C]CH3OTf through O-[(11)C]methylation and isolated by simplified SPE in 40-60% decay corrected radiochemical yields at EOB, with 185-370 GBq/µmol specific activity at EOS.